Full Press Release Details
Corporate Overview - September 2022 Nasdaq: AGLE
Forward Looking Statements 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, our ability to obtain and maintain regulatory approval, the potential therapeutic
benefits, safety profile and economic value of our product candidates, potential growth opportunities, financing plans, use and adequacy of financing plans, the length of time that we believe our existing cash resources will fund operations,
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 candidates pegzilarginase and pegtarviliase
and our other product candidates; 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, including data for our phase 1/2 trial of pegtarviliase (AGLE-177) in Homocystinuria; 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 Annual Report on Form 10-K 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. 2022 Aeglea BioTherapeutics. External 2
Addressing Metabolic Imbalances to Improve the Lives of Patients Our
vision is to redefine the possible, pioneer bold science with human enzymes and deliver groundbreaking medicines that transform lives. We are on a mission to change lives by bringing innovative therapies to underserved rare disease communities.
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Building an Enzyme Therapy Company to Serve Patients and Drive Near and
Long-Term Growth Innovative enzyme engineering platform Differentiated product profiles Pioneering Bold Expertise in metabolic disease and enzyme engineering creates Science complementary opportunities in areas with limited
competition Focused on disease modifying therapies with the potential to change lives Delivering Strong engagement with patient communities to develop products that Groundbreaking meet their needs Medicines Efficient clinical
development and commercialization model Novel approach to unconventional targets - developing treatments for diseases others thought couldn't be addressed with enzyme therapies Redefining the High unmet need and limited
competition drive significant commercial Possible opportunity 2022 Aeglea BioTherapeutics. External 4
Aeglea's Human Enzyme Platform for Rare Metabolic Diseases
Regulatory Addressable Geographic Program Research Phase 1/2 Phase 3 Review Market Rights Pegtarviliase (AGLE-177) Worldwide >30,000 1 rights Patients Homocystinuria Retain rights outside of Europe 3 Pegzilarginase >2,500 and Middle East 2
Patients Arginase 1 Deficiency MAA Validated 5 by EMA Worldwide AGLE-325 >10,000 4 rights Patients Cystinuria Undisclosed Worldwide rights Rare Diseases 1 2 >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 Catsburg C et al 2022 ; Diez- 3 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 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, 4 Kuwait, Bahrain and Oman) 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; 5 Chillar n, 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 Market Authorisation Application (MAA) validated by the European Medicines Agency (EMA) and currently under review; Company
in dialogue with the U.S. Food and Drug Administration following Refusal to File Letter 2022 Aeglea BioTherapeutics. External 5
Program Highlights and Upcoming Milestones Pegtarviliase in
Homocystinuria: Completed cohort 2, currently enrolling cohort 3 Active clinical trial sites in UK, Australia and U.S. Interim clinical data from Phase 1/2 clinical trial expected in fourth quarter of 2022, including data
from cohort 3 Pegzilarginase in ARG1-D: MAA under review with EMA Continuing to engage with FDA to identify potential path to BLA resubmission Corporate: Corporate restructuring prioritizes resources and focus on
pegtarviliase Cost saving measures put in place to extend runway into fourth quarter of 2023 Search for permanent CEO underway; Jim Kastenmayer appointed interim CEO 2022 Aeglea BioTherapeutics. External 6
Pegtarviliase (formerly AGLE-177) - Potential Best-in-Class
Treatment for Homocystinuria
Classical Homocystinuria: A Rare Metabolic Disorder With Serious and
Potentially Deadly Complications Serious Disease Complications Classical Homocystinuria (HCU) Eyes Cystathionine beta synthase (CBS) deficiency, also known as Lens dislocation, glaucoma, severe near-sightedness Classical Homocystinuria, is a serious
and progressive metabolic disorder characterized by elevated levels of the Nervous System Intellectual and amino acid homocysteine. developmental delays, behavioral abnormalities, seizures There are no approved treatments that address
underlying driver of disease - high homocysteine levels Vascular Uncontrolled levels of homocysteine can lead to sudden Life-threatening thrombotic events, heart attack, stroke catastrophic events, including death
Manifestations can occur in early childhood and worsen Skeletal Long bone (Marfanoid) over time features, skeletal deformities, osteoporosis 2022 Aeglea BioTherapeutics. External 8
Inadequate Treatment Options to Control Homocysteine Levels and Prevent
Disease Progression Favorable competitive & regulatory Current standard of care: landscape B6 (pyridoxine) Betaine approved on tHcy lowering alone, Low-methionine diet + amino acid despite limited effectiveness
supplements Small number of treatments currently in clinical Betaine development Current disease management is inadequate with an Current treatment goals focused on achievable, inability to control total homocysteine (tHcy) levels:
not optimal: Limited effectiveness Lowering tHcy levels beyond treatment guidelines has potential to further improve outcomes and change Difficulties with adherence the lives of patients Periods of poor control can
result in catastrophic Strong desire among HCP and patient communities for thromboembolic events and/or life-long impairments more efficacious and less burdensome treatments Poor tolerability of amino acid supplementation and betaine
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Increased Mortality and High Risk of Severe Complications Natural
History Study of 629 Untreated Classical Homocystinuria Patients MORTALITY B6-non-responsive B6-responsive B6-responsive = 231 Elevated levels of homocysteine All patients = 629 Mortality by age 30 23% 4% B6-non-responsive = 231 Most common cause of
death Thromboembolism Lens dislocation in 50% Age 6 Age 10 Median IQ 56 78 Chance of thrombosis by age 15 27% 12% Mudd et al, 1985. Kluijtmans et al, Am. J. Hum. Genet. 65,59-67, 1999 2022 Aeglea BioTherapeutics. CONFEIDNTIAL 10 NATURAL
Sizeable Patient Population and Significant Commercial Opportunity 1
>30,000 Classical HCU patients B6-responsive Currently available treatments work primarily for patients patients considered B6-responsive B6-non-responsive patients and B6-partial responders Partial responders have poorer tHcy
control resulting in more severe 2 disease and significantly worse outcomes B6-non-responsive A large portion of Classical HCU population is in need of patients 2,3 more effective treatment options ~15,000 - 18,000 Significant
Opportunity With Estimated 8,000-8,800 Candidates for Therapy in the U.S., U.K., and EU4 1 2 3 >30,000 represents estimated prevalence of Classical Homocystinuria (including B6-responsive and B6-non-responsive) in 38 addressable markets. Mudd et
al 1985. Ko ich et al, 2020. 4 ~6,000-6,600 represents estimated prevalence of B6-non-responsive Homocystinuria in the U.S (~3,300) and the EU4 plus UK (~3,300); tHcy = total homocysteine 2022 Aeglea BioTherapeutics. External
Pegtarviliase: An Innovative Enzyme Approach to Lowering Homocysteine
Depiction of Normal and Therapeutic Metabolism Pegtarviliase Mechanism Engineered Cystathionine -Lyase (CGL) enzyme mutated to change its native substrate specificity from cystathionine to both homocysteine and its dimer Concentration
gradient drives homocysteine out of tissue and into plasma Equilibrium in plasma in preference of dimer Further metabolism of both monomer and dimer Therapeutic Rationale Elevated levels of plasma homocysteine increase risk for
1 disease manifestations Reduction of plasma homocysteine has been correlated 2 with reduced risk of developing disease manifestations Generally accepted aim of treatment is to lower the plasma homocysteine concentration below
certain thresholds while maintaining normal nutrition 1 2 Mudd, Skovby et al. 1985, Al-Dewik, Ali et al. 2019; Mudd, Skovby et al. 1985, Wilcken and Wilcken 1997, Yap and Naughten 1998 2022 Aeglea BioTherapeutics. External 12
Pegtarviliase Treatment Resulted in Dose-Dependent Response and
Statistically Significant Lowering of Homocysteine in Mouse Model Single Subcutaneous Dose in CBS Experimental Design: 1 Knockout Mouse Model 10-day old CBS knockout mice were 375 dosed with pegtarviliase twice per week for 5 weeks to ensure
they were of a 300 sufficient size Prior to a single SC dose of pegtarviliase, 225 there was a two-week wash out Pegtarviliase (1.0 mg/kg, SC) * * AGLE-17 * * Pegtarviliase (10.0 mg/kg, SC) To ensure accurate tHcy assessment, an 150
AGLE-17 * inhibitor of pegtarviliase was used in * * p < 0.05 by Manley Cox test * the collection tube to block metabolism * 75 2 of tHcy during sample processing 0 24 48 72 96 120 144 168 Hours 1 2 Daige C. et al. Poster presented at ASHG 2020
Virtual Meeting. Thornloe K. et al. Poster presented at ACMG 2022 Meeting' tHcy = total homocysteine; SC = subcutaneous 2022 Aeglea BioTherapeutics. External 13 Plasma tHcy ( M)
Pegtarviliase Treatment Improved Pathologies and Corrects Disease
Manifestations in a Mouse Model of Homocystinuria 2 Reversal of Severe Liver Abnormalities in Beneficial Impact on Osteoporosis 1 CBS Knockout Mouse Model Disease Resolution Disease R eversa l P = 0.0407 p = 0.0407 70 Dosing Begins = Dosing Begins
65 AEB4104 25 mg/kg + AEB4104 25 mg/kg AGLE-177-HIS 25 mg/kg + Healthy liver from AGLE-177-HIS 25 mg/kg Healthy liver from Betaine Day 23 CBS -/- Day 60 CBS -/- 60 Betaine Day 23 CBS-/- wild-type animal Day 60 CBS-/- wild-type animal DD is is ea eas
se P e Prro ogr ges res sis oi n on Day 10 CBS -/- : Day 10 CBS-/- 55 Macro-steatosis Macro-steatosis P P rre em ma atu ture re Death Death 50 PBS + Betaine Day 23 CBS -/- AGLE-177 Vehicle PBS + Betaine Day 23 CBS-/- Micro-steatosis and necrosis 10
mg/kg Macro-steatosis and necrosis Reductions in total plasma homocysteine leads to Increased bone mineral density (BMD) in preclinical model of Homocystinuria with multiple doses improvements in disease-related abnormalities 1 2 Daige C. et al.
Poster presented at ASHG 2018; Daige C. et al. Poster presented at ASHG 2020 Virtual Meeting, CBS -/- mice were dosed SC BIW with AGLE-177 starting at D10 through Day 169 were evaluated for bone mineral density (BMD) by dual-energy X-ray
absorptiometry; AGLE-177-HIS = AGLE-177/pegtarviliase modified to include a polyhistidine tag; CBS -/- = CBS knockout mouse model 2022 Aeglea BioTherapeutics. External 14 2 BMD (mg/cm )
Preclinical Data Support Potential Advantages of Pegtarviliase
Pegtarviliase demonstrated significant survival Pegtarviliase demonstrated pharmacological benefit at substantially lower dose than effect on homocysteine levels in normal animals competitor enzyme that is not seen with competitor enzyme 5 4
Pegtarviliase (10 mg/kg, BIW) V Ve eh hic icl lee Pegtarviliase (3 mg/kg, BIW) 3 A PG egt LE a-r1 v77 ilia 2 s m e 2 m g/kg g/kg Pegtarviliase 6 mg/kg AGLE-177 6 mg/kg Pegtarviliase (1.0 mg/kg, BIW) Pegtarviliase 20 mg/kg AGLE-177 20 mg/kg 2 Vehicle
(BIW) 1 0 0 24 48 72 96 120 144 168 Hours Twice weekly (BIW) subcutaneous doses pegtarviliase in CBS Substantial decreases in homocysteine after single subcutaneous dose 1,3 knockout mouse model in toxicology studies with cynos
(above) and rats (data not shown) Significant survival benefit with pegtarviliase at total weekly Pharmacological effect in normal animals dosed with pegtarviliase 2 dose of 2 mg/kg compared to a total weekly dose of 22.5 mg/kg
differentiated from reported data for a competitor enzyme 2 reported for a competitor enzyme 1 2 3 Daige C. et al. Poster presented at ASHG 2020 Virtual Meeting. Majtan T. et al., Life Sci. 2018; May 1;200:15-25. Mice were 2022 Aeglea
BioTherapeutics. External 15 maintained on betaine until weaning; tHcy = total homocysteine tHcy ( M)
Phase 1/2 Clinical Trial to Generate Proof-of-Concept and Path to
Pivotal Trial PART 1 (IV) PART 2 (SC) Cohort 4 Cohort 5 Cohort 3 (optional) (optional) Currently enrolling Cohort 1 Cohort 2 Dose 0.15 mg/kg Dose 0.45 mg/kg n = 3 n = 4 Endpoints & Design Key Inclusion Criteria Safety and
tolerability Classical HCU diagnosis Interim Clinical Data Expected in Q4 PK Plasma homocysteine >80 M 2022, Including Data From Cohort 3 Reduction in plasma 12 years of age homocysteine levels
4 once weekly doses IV = intravenous; SC = subcutaneous 2022 Aeglea BioTherapeutics. External 16
Pegtarviliase: a Potential Best-in-Class Treatment for Classical
Homocystinuria Preclinical Clinical Demonstrated significant survival benefit in CBS -/- Showed total homocysteine reduction with no mice at low total weekly doses safety concerns at 0.15 mg/kg once weekly in Phase 1/2 trial
Reduced homocysteine levels in CBS -/- mice with single and twice weekly dosing Data suggests once weekly dose schedule Demonstrated potency to reduce homocysteine Toxicology study and initial safety results from normal
levels in normal rats and cynos indicate a large dosing window Pharmacological effects and no significant findings Stable, high-concentration liquid formulation in chronic toxicology studies allows for delivery in single dose
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Pegtarviliase: Preparing to Move Rapidly into Pivotal Trial CMC Phase 3