A Phase 3 Open-Label Study of Safety, Pharmacokinetics, and Activity of Weekly Subcutaneous Pegzilarginase in Subjects <24 Months Old With Arginase 1 Deficiency

This is an open-label, multicentre study to evaluate the safety, PK, and activity (PD) of weekly subcutaneous (SC) administration of pegzilarginase in subjects with ARG1-D who are < 24 months of age. The study consists of a screening period of up to 4 weeks, a subsequent 12-week treatment period, and a safety follow-up period of 8 weeks.

Start Date30 Aug 2024

Sponsor / Collaborator

Immedica Pharma AB

NCT05676853 / TerminatedPhase 3

A Phase 3 Open-Label Study of Safety of Weekly Subcutaneous Pegzilarginase in Subjects With Arginase 1 Deficiency

This is an open-label, multicenter study to evaluate the safety of weekly SC administration of pegzilarginase over 12 months in subjects with ARG1-D. The study consists of a screening period of up to 4 weeks, a subsequent 12-month treatment period, and a Safety Follow-Up Visit 2 weeks after the last treatment.

Start Date04 Apr 2023

Sponsor / Collaborator

Spyre Therapeutics, Inc.

EUCTR2018-004837-34-DE / Not yet recruitingPhase 3

PEACE (Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints): A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of the Efficacy and Safety of Pegzilarginase in Children and Adults with Arginase 1 Deficiency

Start Date20 Jul 2020

Sponsor / Collaborator-

100 Clinical Results associated with Pegzilarginase (Aeglea Biotherapeutics)

100 Translational Medicine associated with Pegzilarginase (Aeglea Biotherapeutics)

100 Patents (Medical) associated with Pegzilarginase (Aeglea Biotherapeutics)

Literatures (Medical) associated with Pegzilarginase (Aeglea Biotherapeutics)

01 Feb 2024·EClinicalMedicine

Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial

Article

Author: Russo, Rossana Sanchez ; Neuman, Linda ; Diaz, George A ; Gasperini, Serena ; Enns, Gregory M ; Bubb, Gillian ; Sloan, Leslie S

Background:

Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. Effective treatments that can lower arginine and improve clinical outcomes is currently lacking. Pegzilarginase is a novel human arginase 1 enzyme therapy. The present trial aimed to demonstrate efficacy of pegzilarginase on pArg and key mobility outcomes.

Methods:

This Phase 3 randomized, double-blind, placebo-controlled, parallel-group clinical trial (clinicaltrials.govNCT03921541, EudraCT 2018-004837-34), randomized patients with ARG1-D 2:1 to intravenously/subcutaneously once-weekly pegzilarginase or placebo in conjunction with their individualized disease management. It was conducted in 7 countries; United States, United Kingdom, Canada, Austria, France, Germany, Italy. Primary endpoint was change from baseline in pArg after 24 weeks; key secondary endpoints were change from baseline at Week 24 in Gross Motor Function Measure part E (GMFM-E) and 2-min walk test (2MWT). Full Analysis Set was used for the analyses.

Findings:

From 01 May 2019 to 29 March 2021, 32 patients were enrolled and randomized (pegzilarginase, n = 21; placebo, n = 11). Pegzilarginase lowered geometric mean pArg from 354.0 μmol/L to 86.4 μmol/L at Week 24 vs 464.7 to 426.6 μmol/L for placebo (95% CI: -67.1%, -83.5%; p < 0.0001) and normalized levels in 90.5% of patients (vs 0% with placebo). In addition, clinically relevant functional mobility improvements were demonstrated with pegzilarginase treatment. These effects were sustained long-term through additional 24 weeks of subsequent exposure. Pegzilarginase was well-tolerated, with adverse events being mostly transient and mild/moderate in severity.

Interpretation:

These results support pegzilarginase as the first potential treatment to normalize pArg in ARG1-D and achieve clinically meaningful improvements in functional mobility.

Funding:

Aeglea BioTherapeutics.

01 Jan 2022·Lung Cancer-Targets and Therapy

Arginine Deprivation in SCLC: Mechanisms and Perspectives for Therapy.

Review

Author: Carpentier, Joséphine ; Pavlyk, Iuliia ; Szlosarek, Peter W ; Hall, Peter E ; Mukherjee, Uma

Arginine deprivation has gained increasing traction as a novel and safe antimetabolite strategy for the treatment of several hard-to-treat cancers characterised by a critical dependency on arginine. Small cell lung cancer (SCLC) displays marked arginine auxotrophy due to inactivation of the rate-limiting enzyme argininosuccinate synthetase 1 (ASS1), and as a consequence may be targeted with pegylated arginine deiminase or ADI-PEG20 (pegargiminase) and human recombinant pegylated arginases (rhArgPEG, BCT-100 and pegzilarginase). Although preclinical studies reveal that ASS1-deficient SCLC cell lines are highly sensitive to arginine-degrading enzymes, there is a clear disconnect with the clinic with minimal activity seen to date that may be due in part to patient selection. Recent studies have explored resistance mechanisms to arginine depletion focusing on tumor adaptation, such as ASS1 re-expression and autophagy, stromal cell inputs including macrophage infiltration, and tumor heterogeneity. Here, we explore how arginine deprivation may be combined strategically with novel agents to improve SCLC management by modulating resistance and increasing the efficacy of existing agents. Moreover, recent work has identified an intriguing role for targeting arginine in combination with PD-1/PD-L1 immune checkpoint inhibitors and clinical trials are in progress. Thus, future studies of arginine-depleting agents with chemoimmunotherapy, the current standard of care for SCLC, may lead to enhanced disease control and much needed improvements in long-term survival for patients.

01 Jul 2021·Journal of inherited metabolic diseaseQ2 · MEDICINE

Clinical effect and safety profile of pegzilarginase in patients with arginase 1 deficiency

Q2 · MEDICINE

Article

Author: Schulze, Andreas ; Bubb, Gillian ; Zori, Roberto T. ; Diaz, George A. ; Quinn, Anthony G. ; Enns, Gregory M. ; Leão‐Teles, Elisa ; Merritt, J. Lawrence ; McNutt, Markey C. ; Bannick, Allison ; Potts, Susan L. ; Sloan, Leslie S. ; Batzios, Spyros

Abstract:

Hyperargininemia in patients with arginase 1 deficiency (ARG1‐D) is considered a key driver of disease manifestations, including spasticity, developmental delay, and seizures. Pegzilarginase (AEB1102) is an investigational enzyme therapy which is being developed as a novel arginine lowering approach. We report the safety and efficacy of intravenously (IV) administered pegzilarginase in pediatric and adult ARG1‐D patients (n = 16) from a Phase 1/2 study (101A) and the first 12 weeks of an open‐label extension study (102A). Substantial disease burden at baseline included lower‐limb spasticity, developmental delay, and previous hyperammonemic episodes in 75%, 56%, and 44% of patients, respectively. Baseline plasma arginine (pArg) was elevated (median 389 μM, range 238‐566) on standard disease management. Once weekly repeat dosing resulted in a median decrease of pArg of 277 μM after 20 cumulative doses (n = 14) with pArg in the normal range (40 to 115 μM) in 50% of patients at 168 hours post dose (mean pegzilarginase dose 0.10 mg/kg). Lowering pArg was accompanied by improvements in one or more key mobility assessments (6MWT, GMFM‐D & E) in 79% of patients. In 101A, seven hypersensitivity reactions occurred in four patients (out of 162 infusions administered). Other common treatment‐related adverse events (AEs) included vomiting, hyperammonemia, pruritus, and abdominal pain. Treatment‐related serious AEs that occurred in five patients were all observed in 101A. Pegzilarginase was effective in lowering pArg levels with an accompanying clinical response in patients with ARG1‐D. The improvements with pegzilarginase occurred in patients receiving standard treatment approaches, which suggests that pegzilarginase could offer benefit over existing disease management.

News (Medical) associated with Pegzilarginase (Aeglea Biotherapeutics)

29 Feb 2024

·www.prnewswire.com

Spyre Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Provides Corporate Update

Announced corporate name change to Spyre Therapeutics; appointment of Cameron Turtle, DPhil, as Chief Executive Officer; and began trading on Nasdaq under the symbol "SYRE" SPY001, an anti-α4β7 antibody engineered for infrequent, subcutaneous dosing, demonstrated an updated half-life of 22 days, a greater than three-fold increase relative to vedolizumab in non-human primate pharmacokinetic data recently presented at ECCO; remains on track to begin first-in-human studies in the first half of 2024, with interim proof-of-concept data expected year-end 2024 SPY002, an anti-TL1A antibody designed for enhanced potency to both TL1A monomers and trimers, and extended half-life compared to existing molecules, remains on track to begin first-in-human studies in the second half of 2024 Raised $180 million in private placement equity financing with participation from new and existing investors $340 million of cash, cash equivalents, marketable securities, and restricted cash as of December 31, 2023, with expected runway into the second half of 2026, through multiple clinical readouts WALTHAM, Mass., Feb. 29, 2024 /PRNewswire/ -- Spyre Therapeutics, Inc. ("Spyre" or the "Company") (NASDAQ:SYRE), a biotechnology company advancing a pipeline of investigational antibody therapeutics with the potential to transform the treatment of inflammatory bowel disease ("IBD"), today announced its fourth quarter and full year 2023 financial results and provided program and corporate updates. "In 2023, we built the foundation required to advance our mission of creating IBD therapies that provide meaningful improvements in both efficacy and convenience compared to today's standard of care. Beginning with a highly unique portfolio of three promising drug candidates to what we consider the most critical targets in IBD, including α4β7, TL1A, and IL-23, we capitalized the company with nearly $400 million from top-tier investors while also attracting a talented and passionate management team and Board of Directors," said Cameron Turtle, DPhil., Chief Executive Officer. "As we look forward to 2024, our ambitions will come into focus as we enter clinical studies across multiple programs and begin to demonstrate potential best-in-class properties of our investigational medicines. We anticipate initiating Phase 2 evaluation of rational therapeutic combinations in IBD patients in 2025." Development Pipeline Overview and Update The Company's approach combines best-in-class antibody engineering, rational therapeutic combinations, and precision immunology with the goal of maximizing efficacy, safety, and convenience of its IBD treatments under development. IBD is a chronic condition characterized by inflammation within the gastrointestinal tract, including two main disorders: ulcerative colitis ("UC") and Crohn's disease ("CD"). In the United States, it is estimated that approximately 2.4 million individuals are diagnosed with IBD. The Company has four programs in preclinical development, three of which are targets in IBD validated by third parties. The fourth program is a novel, undisclosed target. The Company is also researching rational combinations of its therapeutic antibody product candidates to target IBD. All three validated targets offer the potential for effective and safe treatment of UC and CD as a monotherapy or in combination, with the potential advantage of infrequent subcutaneous dosing. SPY001 – a highly potent and selective investigational anti-α4β7 monoclonal antibody engineered with half-life extension technology and formulated for high concentration and subcutaneous, infrequent dosing. In the third quarter of 2023, the Company selected the SPY001 development candidate, which is currently progressing through IND-enabling studies and is expected to enter first-in-human ("FIH") studies in the first half of 2024. In February 2024, expanded preclinical data for SPY001 was presented at the 19th Annual Congress of the European Crohn's and Colitis Organisation (ECCO), including head-to-head non-human primate pharmacokinetic data showing an updated half-life of 22 days, a greater than three-fold increase relative to vedolizumab. This data further supports our target human half-life for SPY001 of more than 35 days predicted by allometric scaling. Interim data from a healthy volunteer study are expected by the end of 2024. The Company expects pharmacokinetic data to demonstrate proof of concept for SPY001 to potentially be dosed subcutaneously in an every-eight-week or every-twelve-week dosing interval. SPY002 – a highly potent, selective, half-life extended, anti-TL1A investigational monoclonal antibody with potential best-in-class subnanomolar binding affinity for both the monomer and trimer forms of the target. The Company believes TL1A has emerged as one of the most promising targets in IBD and broader immunology indications. The Company has nominated two lead SPY002 development candidates and exercised its option to exclusively license related intellectual property rights under its agreement with Paragon Therapeutics. The Company's lead candidates bind both TL1A monomers and trimers and have in vitro subnanomolar potency and pharmacokinetic half-lives that potentially exceed all clinical-stage TL1A antibodies. In February 2024, preclinical data for a lead SPY002 development candidate was presented at the 19th Annual ECCO Congress demonstrating subnanomolar binding affinity and potency, as well as a pharmacokinetic half-life of 24 days in non-human primates, which represents a two to three-fold increase compared to clinical-stage anti-TL1As. The Company expects to begin FIH studies of one or both SPY002 candidates in the second half of 2024 with healthy volunteer interim data expected in the first half of 2025. If successful, one SPY002 candidate would then advance into additional clinical development. SPY003 – a highly potent and selective investigational monoclonal antibody targeting the p19 subunit of IL-23 engineered with half-life extension technology. The Company continues preclinical development efforts on a potential best-in-class IL-23 monoclonal antibody. Recent data from the Phase 3 SEQUENCE study of risankizumab versus ustekinumab in Crohn's disease validates the Company's targeting of the p19 subunit as it demonstrated superiority to targeting the p40 subunit common to IL-12 and IL-23. The Company expects to nominate a development candidate in mid-2024 and move into IND-enabling studies in the second half of 2024. Recent Corporate Updates In February 2024, the Company announced the appointment of Mark C. McKenna, former Chairman, President and CEO of Prometheus Biosciences, Inc., to its Board of Directors. Mr. McKenna's track record of corporate leadership, product development, and value creation will be instrumental to guide the Company as it advances its potentially best-in-class IBD portfolio. In December 2023, the Company announced $180 million in gross proceeds from a private placement equity financing with broad participation from both new and existing investors, extending cash runway into the second half of 2026. In November 2023, the Company announced its name change to Spyre Therapeutics and the appointment of Cameron Turtle as Chief Executive Officer and also a member of the Company's Board of Directors. The Company also announced the appointments of industry veterans Jeffrey Albers and Laurie Stelzer to its Board of Directors. In November 2023, the Company held a Special Meeting of Stockholders wherein all four proposals were approved, including the conversion of the Company's Series A Preferred Stock to common stock and an increase to the Company's authorized shares. Fourth Quarter 2023 Financial Results Cash Position: As of December 31, 2023, Spyre had available cash and cash equivalents, marketable securities, and restricted cash of $339.6 million. Net cash used in operating activities was $31.0 million for the fourth quarter of 2023. In December 2023, the Company raised $180.0 million in gross proceeds, before deducting $10.9 million in placement agent fees and other offering costs, from a private placement of equity securities. Research and Development (R&D) expenses: R&D expenses totaled $33.7 million for the fourth quarter of 2023 and $14.3 million for the fourth quarter of 2022. The increase was primarily related to increases in preclinical development and manufacturing expenses for the Company's IBD pipeline including expenses related to the annual equity grant under our agreement with Paragon, partially offset by a decrease in expenses associated with the Company's legacy rare disease pipeline. General and Administrative (G&A) expenses: G&A expenses totaled $14.1 million for the fourth quarter of 2023 and $5.1 million for the fourth quarter of 2022. This increase was primarily due to an increase in stock compensation expense, as well as legal and other professional service fees related to the Spyre acquisition. Gain on Sale of In-Process Research & Development Asset: During the fourth quarter of 2023, the Company recognized an additional $1.8 million gain on the sale of the global rights of pegzilarginase driven by the receipt of a cash reimbursement from Immedica for a previous expenditure. Other (expense) income: Other (expense) income for the fourth quarter totaled $17.3 million expense primarily driven by an increase in the Company's CVR liability related to the increased likelihood of certain milestone payments related to pegzilarginase reimbursement in European markets, partially offset by interest earned on the Company's cash and marketable securities. Net Loss: Net loss totaled $63.2 million and $18.8 million for the fourth quarters of 2023 and 2022, respectively, which includes non-cash stock compensation expense of $17.3 million and $1.4 million for the fourth quarters of 2023 and 2022, respectively. About Spyre Therapeutics Spyre Therapeutics is a biotechnology company that aims to create the next-generation of inflammatory bowel disease (IBD) products by combining best-in-class antibody engineering, rational therapeutic combinations, and precision medicine approaches. Spyre's pipeline includes investigational extended half-life antibodies targeting α4β7, TL1A, and IL-23. For more information, please visit . Follow Spyre Therapeutics on social media: @spyretx and LinkedIn. 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. All statements contained in this press release, other than statements of historical fact are forward-looking statements. These forward-looking statements include statements regarding the Company's future results of operations and financial position, business strategy, including the Company's potential success of developing therapeutics for IBD, the sufficiency of the Company's funding to support the development of its assets, the length of time that the Company believes its existing cash resources will fund its operations, its market size, its potential growth opportunities, its preclinical and future clinical development activities, including the expected timing of nomination of development candidates and submission of investigational new drug applications, the efficacy and safety profile of its product candidates, the potential therapeutic benefits and economic value of its product candidates, the timing and results of preclinical studies and clinical trials, including the commencement of FIH studies, the timing of data and whether the data demonstrates proof of concept, and the Company's planned regulatory activities including filing of INDs to support development and potential commercialization of product candidates. The words "believe," "may," "will," "potentially," "estimate," "continue," "anticipate," "predict," "target," "intend," "could," "would," "should," "project," "plan," "expect," the negatives of these terms, and similar expressions that convey uncertainty of future events or outcomes are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including the expected or potential impact of macroeconomic conditions, including inflationary pressures, rising interest rates, general economic slowdown or a recession, changes in monetary policy, the prospect of a shutdown of the U.S. federal government, volatile market conditions, financial institution instability, as well as geopolitical instability, including the ongoing military conflict in Ukraine, conflict in Israel and surrounding areas, and geopolitical tensions in China on the Company's operations, the potential impacts of the BIOSECURE Act bill if passed into law and those risks described in the Company's Quarterly Reports on Form 10-Q, Annual Reports on Form 10-K, as well as in other filings and reports that the Company makes from time to time with the Securities and Exchange Commission. Moreover, the Company operates in a very competitive and rapidly changing environment, and new risks emerge from time to time. It is not possible for the Company's management to predict all risks, nor can the Company assess the impact of all factors on the 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 it may make. In light of these risks, uncertainties, and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, the Company cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. The Company undertakes no obligation to update publicly any forward-looking statement for any reason after the date of this press release to conform these statements to actual results, to reflect changes in the Company's expectations, or otherwise, except as required by law. You should read press release with the understanding that the Company's actual results, levels of activity, performance, events, outcomes, and the timing of results and outcomes, and other circumstances may be materially different from what the Company expects. SOURCE Spyre Therapeutics, Inc.

Executive ChangeFinancial StatementPhase 2

09 Nov 2023

·www.prnewswire.com

Aeglea BioTherapeutics Reports Third Quarter 2023 Financial Results and Provides Corporate Update

Continued progress across the Company's potentially best-in-class inflammatory bowel disease (IBD) portfolio SPY001, a half-life extended anti-α4β7 antibody, is on track for an expected IND filing in the first half of 2024, with interim healthy volunteer, proof of concept pharmacokinetic data expected year-end 2024 SPY002, a half-life extended anti-TL1A antibody with potential best-in-class picomolar binding affinity for both the monomer and trimer forms of the target, is on track for expected IND filing in the second half of 2024 Stockholder vote scheduled for November 21 to allow conversion of preferred stock to common stock Strengthened leadership team with the appointments of Scott Burrows as Chief Financial Officer and Heidy King-Jones as Chief Legal Officer and Corporate Secretary $205 million of cash, cash equivalents, marketable securities, and restricted cash as of September 30, 2023, with expected runway into 2026 WALTHAM, Mass., Nov. 9, 2023 /PRNewswire/ -- Aeglea BioTherapeutics, Inc. ("Aeglea" or the "Company") (NASDAQ:AGLE), a biotechnology company advancing a pipeline of antibody therapeutics with the potential to transform the treatment of inflammatory bowel disease ("IBD"), today announced its third quarter 2023 financial results and provided program and corporate updates. "We have made significant progress in our first quarter following the Spyre acquisition towards our goal of creating new, best-in-class medicines for patients with IBD. We believe that our combination strategy and pipeline, including SPY001, an extended half-life anti-α4β7 antibody, and SPY002 a dual monomer / trimer anti-TL1A antibody with picomolar affinity and extended half-life, offer the potential to meaningfully improve both efficacy and convenience relative to today's standard of care," said Cameron Turtle, D.Phil., Chief Operating Officer of Aeglea. "In addition to progressing our portfolio towards first-in-human studies next year, we have built out our team with passionate and experienced biotechnology leaders." Development Pipeline Overview and Update With its acquisition of Spyre Therapeutics, Inc. ("Spyre") in June 2023, Aeglea shifted its disease focus to IBD. The Company's approach combines best-in-class antibody engineering, rational therapeutic combinations, and precision immunology with the goal of maximizing efficacy, safety, and convenience of its IBD treatments under development. IBD is a chronic condition characterized by inflammation within the gastrointestinal tract, including two main disorders: ulcerative colitis ("UC") and Crohn's disease ("CD"). In the United States, it is estimated that approximately 2.4 million individuals are diagnosed with IBD. The Company has four product candidates in preclinical development, three of which are validated targets in IBD. The fourth product candidate is a novel, undisclosed target. SPY001 – a highly potent and selective anti-α4β7 monoclonal antibody engineered with half-life extension technology and formulated for high concentration, convenient dosing. SPY001 is currently progressing through IND-enabling studies and is expected to enter first-in-human ("FIH") studies in the first half of 2024. Interim data from a healthy volunteer study are expected by the end of 2024. The Company expects pharmacokinetic data to demonstrate proof of concept for its ability to potentially reach an every-eight-week or every-twelve-week dosing interval. SPY002 – a highly potent and selective anti-TL1A monoclonal antibody engineered with half-life extension technology. The Company believes TL1A has emerged as one of the most promising targets in IBD and broader immunology indications. The Company's extensive discovery campaign has identified lead clones which bind both TL1A monomers and trimers with picomolar affinity and have in vitro potency and pharmacokinetic half-lives that exceed all clinical-stage TL1A antibodies. The Company expects to begin FIH studies of the SPY002 program in the second half of 2024 with healthy volunteer interim data expected in the first half of 2025. SPY003 – a highly potent and selective monoclonal antibody targeting the p19 subunit of IL-23 engineered with half-life extension technology. The Company continues preclinical development efforts on a potential best-in-class IL-23 monoclonal antibody. Recent data from the Phase 3 SEQUENCE study of risankizumab versus ustekinumab in Crohn's disease validates the Company's targeting of the p19 subunit as it demonstrated superiority to targeting the p40 subunit of IL-23. An IND/CTN is expected in 2025. Corporate Updates In October 2023, the Company filed a definitive proxy statement regarding the Special Meeting of Stockholders to be held on November 21, 2023 (the "Special Meeting"). At the Special Meeting, stockholders are expected to vote on four proposals, including the conversion of the Company's Series A Preferred Stock to common stock and an increase to the Company's authorized shares. In September 2023, the Company strengthened its leadership team with the appointments of industry veterans Scott Burrows, as Chief Financial Officer, and Heidy Abreu King-Jones, as Chief Legal Officer and Corporate Secretary. In September 2023, the Company completed a reverse stock split of all outstanding shares of common stock at a ratio of 1-for-25, with trading on a split-adjusted basis on the Nasdaq Capital Market beginning on September 8, 2023. In July 2023, the Company sold the global rights to pegzilarginase to Immedica Pharma AB ("Immedica") for $15 million in upfront cash proceeds and up to $100 million in contingent milestone payments. In November 2023, holders of the Company's contingent value rights (CVRs) are expected to receive a payment representing the Immedica sale proceeds net of expenses and adjustments pursuant to the CVR agreement entered into in connection with Aeglea's acquisition of Spyre. Third Quarter 2023 Financial Results Cash Position: As of September 30, 2023, Aeglea had available cash and cash equivalents, marketable securities, and restricted cash of $204.9 million. Research and Development (R&D) expenses: R&D expenses totaled $24.7 million for the third quarter of 2023 and $12.0 million for the third quarter of 2022. This increase was primarily related to increases in preclinical development and manufacturing expenses for the Company's IBD pipeline, partially offset by a decrease in expenses associated with the legacy Aeglea rare disease pipeline. General and Administrative (G&A) expenses: G&A expenses totaled $8.6 million for the third quarter of 2023 and $7.0 million for the third quarter of 2022. This increase was primarily due to an increase in legal and employee separation costs. Gain on Sale of In-Process Research & Development Asset: During the third quarter of 2023, the Company recognized a $14.6 million gain on the sale of the global rights of pegzilarginase to Immedica. Other Income and Expenses: Other Income and Expenses were a net $21.8 million expense in the third quarter of 2023, primarily driven by a $25.4 million non-cash forward contract liability expense related to an increase in fair value of the underlying Series A Preferred Stock between June 30, 2023 and the forward contract's settlement on July 7, 2023. Net Loss: Net loss totaled $40.1 million and $18.2 million for the third quarter of 2023 and 2022, respectively, which includes non-cash stock compensation expense of $4.8 million and $1.6 million for the third quarter of 2023 and 2022, respectively. About Aeglea BioTherapeutics In June 2023, Aeglea completed the asset acquisition of Spyre and shifted its disease focus to IBD. Aeglea is advancing a pipeline of antibody therapeutics with the potential to transform the treatment of IBD. Aeglea's approach combines novel antibody engineering, rational therapeutic combinations, and precision immunology with the goal of maximizing efficacy, safety, and convenience of treatments for IBD. The company is developing antibodies targeting α4β7, TL1A, and IL-23. For more information, please visit . Follow Aeglea BioTherapeutics on social media: @aegleabio and LinkedIn. 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. All statements contained in this press release, other than statements of historical fact are forward-looking statements. These forward-looking statements include statements regarding stockholder approval of the conversion rights of the Series A Preferred Stock, any future payouts under the non-transferable contingent value right agreement (the "CVR Agreement"), the Company's ability to achieve the expected benefits or opportunities and related timing with respect to its asset acquisition of Spyre or to monetize its legacy assets, its future results of operations and financial position, business strategy, including the success of its refocus towards developing therapeutics for IBD, the length of time that the Company believes its existing cash resources will fund its operations, its market size, its potential growth opportunities, its preclinical and future clinical development activities, including the expected timing of submission of investigational new drug applications, the efficacy and safety profile of its product candidates, the potential therapeutic benefits and economic value of its product candidates, the timing and results of preclinical studies and clinical trials, including the timing of interim data and whether the data demonstrates proof of concept, the expected impact of macroeconomic conditions, including inflationary pressures, rising interest rates, general economic slowdown or a recession, changes in monetary policy, the prospect of a shutdown of the U.S. federal government, volatile market conditions, financial institution instability, as well as geopolitical instability, including the ongoing military conflict in Ukraine, conflict in Israel and surrounding areas, and geopolitical tensions in China on its operations, and the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates. The words "believe," "may," "will," "potentially," "estimate," "continue," "anticipate," "predict," "target," "intend," "could," "would," "should," "project," "plan," "expect," the negatives of these terms, and similar expressions that convey uncertainty of future events or outcomes are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including those described in the Company's Quarterly Reports on Form 10-Q, Annual Reports on Form 10-K, as well as in other filings and reports that the Company makes from time to time with the Securities and Exchange Commission. Moreover, the Company operates in a very competitive and rapidly changing environment, and new risks emerge from time to time. It is not possible for the Company's management to predict all risks, nor can the Company assess the impact of all factors on the 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 it may make. In light of these risks, uncertainties, and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, the Company cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. The Company undertakes no obligation to update publicly any forward-looking statement for any reason after the date of this press release to conform these statements to actual results, to reflect changes in the Company's expectations, or otherwise, except as required by law. You should read press release with the understanding that the Company's actual results, levels of activity, performance, events, outcomes, and the timing of results and outcomes, and other circumstances may be materially different from what the Company expects. SOURCE Aeglea BioTherapeutics, Inc.

Executive ChangeAcquisitionPhase 3Financial Statement

16 Oct 2023

·www.biospace.com

Experts Implore FDA to Accept Biomarker Evidence in Ultra-Rare Diseases

Pictured: A rare disease awareness ribbon with a diverse representation of people/iStock, nambitomo Arginase 1 deficiency, or ARG1-D, is a rare, inherited disorder occurring in approximately 1.1 in 1 million live U.S. births. While born with normal function, by the age of two, patients with the condition have progressive deterioration in their physical ability due to the gradual accumulation of arginine and ammonia in the blood. The nervous system is particularly sensitive to high levels of ammonia, Stephen Cederbaum, a UCLA professor emeritus who has studied ARG1-D for more than 50 years, told BioSpace. Untreated, children progressively deteriorate, experiencing spasticity and developmental delays. There is currently no disease-modifying treatment for ARG1-D. Stephen Cederbaum So it may have seemed like welcome news for ARG1-D patients and their families when an experimental drug, pegzilarginase, developed by Aeglea BioTherapeutics, was found to rapidly and sustainably lower arginine levels and elicit improvements in mobility. A novel, recombinant human arginase 1 enzyme, pegzilarginase led to a statistically significant 80% reduction in mean plasma arginine—a key biomarker—in the pivotal Phase III PEACE trial; 90.5% of patients treated with the enzyme achieved normal plasma arginine levels compared to none on placebo. Then, last June, the company received a Refusal to File letter from the FDA in response to its Biologics License Application for pegzilarginase. The FDA requested more data to support its efficacy—particularly evidence showing that plasma arginine and metabolite reduction could predict clinical benefit in patients with ARG1-D. Aeglea has since sold the rights to the drug to its European partner, Immedica Pharma, but a group of experts is appealing to the FDA to give it another shot. These experts, including Cederbaum, believe the FDA should leverage its accelerated approval pathway, which allows the regulator to exercise flexibility when a treatment proposed for a serious disease or condition demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. “What we’re appealing [for] is accelerated approval,” said Cederbaum, who served as a one-time consultant to Aeglea and has followed the drug’s saga closely. “Given what we now know, and what has been demonstrated for us . . . when we get some of these patients back on therapy, they’re going to be the living proof that [pegzilarginase] really does help.” Barriers to Approval The reason the PEACE trial failed to meet the FDA’s bar for approval, Cederbaum said, is that many of the patients were older and had been diagnosed symptomatically only after severe and irreversible brain damage had occurred. PEACE enrolled 32 patients two years and older. Cederbaum and his colleagues have collected video evidence showing that participants in Aeglea’s extension trials have deteriorated since going off of pegzilarginase. “In one case, a patient had not gotten particularly better, but when he got off the enzyme, he really just collapsed,” Cederbaum said. While the team feels they have substantial evidence to go back to the FDA, “what we’re now lacking is a supply of enzyme and a company to champion this.” Cederbaum said he believes the FDA’s skepticism regarding pegzilarginase comes down to the question: has it been proven that increased levels of arginine and ammonia are the cause of ARG1-D and that bringing these levels down to normal is absolutely certain to be beneficial? The answer to that question, he said, is no. But “There is a mechanism now for dealing with this uncertainty, and that is accelerated approval.” Emil Kakkis Emil Kakkis, founder, president and CEO of Ultragenyx, a company that develops medicines for patients with rare and ultrarare diseases but has no direct involvement with Aeglea or Immedica, told BioSpace he got involved with the campaign for the drug’s approval because “I felt like arginase, if anything, is a poster child for the failure to use accelerated approval correctly at FDA.” When asked by BioSpace if the FDA would consider showing flexibility in the case of pegzilarginase, an agency representative declined to comment on this case specifically but said that the FDA “recognizes the importance of facilitating the development of, and access to, safe and effective treatment options for life-threatening and severely debilitating diseases with unmet medical needs, such as arginase 1 deficiency. “As such, we apply flexibility in these situations to address the particular challenges posed by each disease while upholding our regulatory standards,” the representative said. While Kakkis said the FDA requested a trial longer than six months, he noted that getting 30 patients into a trial “was already a miracle.” With “a handful of patients” in the U.S. and at a cost of $300,000 to $500,000 per patient per year, it would be impossible to conduct another trial, he said. The only reason Aeglea was able to fund a pivotal trial with 30 patients is that when the company started in 2013, “the stock market was up in the biotech space, and they were able to raise money to work on a disease this rare.” Today, he said, that money doesn’t exist, and there is no way for a company to see a return on its investment. The other problem with a longer trial, Kakkis said, is “If within six months, you know that the treated group is 90% normalized, it’s kind of unethical to keep the other group on placebo for a long period of time.” Kakkis recommended that the FDA consider data from the open-label extension (OLE) study of Aeglea’s Phase I/II trial, where 13 patients were treated with pegzilarginase plus standard-of-care for 96 weeks. In an abstract of the study, published this year, the authors concluded that “clinically meaningful improvements in functional mobility” increased with continued pegzilarginase treatment. At the time of Aeglea’s BLA submission, 56-week data from this study was available. The BLA also included data from the ongoing OLE of the PEACE trial. A Fundamental Problem Kakkis is the author of Saving Ryan, which documents his race—along with Ryan’s father, Mark Dant—to gain approval for the first-ever treatment for mucopolysaccharidoses (MPS), a group of inherited lysosomal storage disorders. “From that experience . . . I fundamentally recognized that there is a problem at FDA with dealing with ultra-rare diseases: scientifically knowing what to do with them, interpreting data and just a sort of cynical attitude,” he said. The MPS treatment, Aldurazyme, was eventually developed by BioMarin and Genzyme and won FDA approval in 2003, “But honestly, it barely made it,” Kakkis said, due to what he called “obstruction of biomarker acceptance” by the regulator. In 2009, Kakkis founded the EveryLife Foundation to accelerate innovation for rare diseases, which launched a campaign called CureTheProcess. The campaign, Kakkis said, focused on increasing FDA expertise in reviewing rare disease drugs and encouraging the regulator to accept alternative study designs and biomarkers “when the science underpinning them is very strong.” The FDA representative said the agency “recognizes the unique challenges in rare disease product development and encourages drug developers to consider and discuss with FDA alternative study designs and biomarkers” for the development of these drugs. Pegzilarginase is currently under review by the European Medicines Agency, and when announcing the sale of the rights to pegzilarginase to Immedica, Aeglea president and CFO Jonathan Alspaugh said the Swedish company would “seek to continue the dialogue with the FDA to discuss a path forward for [the drug] in the United States.” Kakkis said the regulatory acceptance of biomarkers is critical in ultra-rare diseases. When dealing with a disease marker that represents the underlying disease, he said, “It’s not a random secondary measure. It’s actually the source of the disease.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and X @chicat08.

Clinical ResultPhase 3Drug ApprovalAccelerated Approval

100 Deals associated with Pegzilarginase (Aeglea Biotherapeutics)

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KEGG	Wiki	ATC	Drug Bank
D11695	-	-	DB14780

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Hyperargininemia	EU	Immedica Pharma AB	15 Dec 2023
Hyperargininemia	IS	Immedica Pharma AB	15 Dec 2023
Hyperargininemia	LI	Immedica Pharma AB	15 Dec 2023
Hyperargininemia	NO	Immedica Pharma AB	15 Dec 2023

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Extensive stage Small Cell Lung Cancer	Phase 2	US	Spyre Therapeutics, Inc.	21 Dec 2017
Extensive stage Small Cell Lung Cancer	Phase 2	PR	Spyre Therapeutics, Inc.	21 Dec 2017
Refractory acute myeloid leukemia	Phase 2	US	Spyre Therapeutics, Inc.	01 Aug 2016
Refractory acute myeloid leukemia	Phase 2	CA	Spyre Therapeutics, Inc.	01 Aug 2016
Refractory Myelodysplastic Syndrome	Phase 2	US	Spyre Therapeutics, Inc.	01 Aug 2016
Refractory Myelodysplastic Syndrome	Phase 2	CA	Spyre Therapeutics, Inc.	01 Aug 2016
Relapsing acute myeloid leukemia	Phase 2	US	Spyre Therapeutics, Inc.	01 Aug 2016
Relapsing acute myeloid leukemia	Phase 2	CA	Spyre Therapeutics, Inc.	01 Aug 2016
Advanced Malignant Solid Neoplasm	Phase 2	US	Spyre Therapeutics, Inc.	01 Oct 2015

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03921541 (PEACE, CTgov)	Phase 3	Hyperargininemia	32	Pegzilarginase (Pegzilarginase)	idwuivfcul(ecezlszjjq) = stubefbbqy cphkpwybif (clmdghkmgk, zhjhhvvjcr - pvzkroqtaw) View more	-	19 Nov 2024
NCT03921541 (PEACE, CTgov)	Phase 3	Hyperargininemia	32	Placebo (Placebo)	idwuivfcul(ecezlszjjq) = btvhfxpesm cphkpwybif (clmdghkmgk, qsniojlfbr - racetgxoxm) View more	-	19 Nov 2024
NCT03921541 (PEACE, SSIEM2022)	Phase 3	Hyperargininemia plasma arginine (pArg)	32	Pegzilarginase	ltmlnaokzi(vfddfmqulc) = tqtometype gywkdhbymh (mctddsketg )	Positive	30 Aug 2022
NCT03378531 \| NCT02488044 (Pubmed \| J Inherit Metab Dis) Manual	Phase 1/2	Hyperargininemia	16	pegzilarginase	vdmvcxfgma(zmhlauxeou) = five patients were all observed in 101A pzlcwnexyk (scnoirrukx ) View more	Positive	01 Jul 2021
EAN2020	Not Applicable	Hyperargininemia	-	Pegzilarginase	vxaqedsxtn(npaljeamqv) = mean change 46m zrbcifxkmw (iiwirceaib ) View more	-	22 May 2020
SSIEM2019	Phase 1/2	Hyperargininemia plasma arginine	16	Pegzilarginase	hspsjajhen(tmbxtopuwr) = bwaiuzqffg ymxqjsbehv (hnzwzzdrtz )	-	25 Aug 2019
SITC2018	Not Applicable	Neoplasms L-Arginine	-	Anti-PD-L1 Ab	etgbdwwnsk(anfdwfzknv) = rafshpnggy qtybzoaxeo (iaxnyuqahx )	Positive	06 Nov 2018
SITC2018	Phase 1	Neoplasms	-	Pegzilarginase	ebrbjfkbqv(bjedlxuvxg) = increased levels of granzyme A, IFN-g and TNF-a yraehweqfd (sgonnpzqqh ) View more	Positive	06 Nov 2018
SITC2018	Phase 1	Neoplasms	-	aOX40 mAb		Positive	06 Nov 2018
NCT02561234 (AACR2018) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	40	pegzilarginase	fzdxtmaqfh(qqzgrsutmr) = 0.33 mg/kg once weekly osmmviuajr (cjoklzzuwe ) View more	Positive	01 Jul 2018
NCT02732184 (ASCO2018) Manual	Phase 1	Refractory acute myeloid leukemia \| Myelodysplastic Syndromes	21	pegzilarginase	iignwsourz(mbrnwqiohw) = bsodfbpgcs cmdaxejxxi (chosyfybur )	Positive	04 Jun 2018

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