Spyre Therapeutics, Inc.
For the period ended Jun 30, 2025. Filed Aug 5, 2025.
View on SEC.govAbout this filing
A company's report for each of its first three quarters. The financial statements are not audited. It shows how the business has moved since the last annual report, and what management says changed.
Jun 30, 2025 · Filed Aug 5, 2025
SYRE$103.86+7.5%Stored close · as of Nov 6, 2026
What changed in Management’s Discussion and Analysis?
Read the current filingPrevious report: 10-Q
Period ended 2025-03-31; filed 2025-05-08.
0001636282-25-000049
Item 2. Management’s Discussion and Analysis of Financial Condition and Results of OperationsCurrent report: 10-Q
Period ended 2025-06-30; filed 2025-08-05.
0001636282-25-000089
Item 2. Management’s Discussion and Analysis of Financial Condition and Results of OperationsThe baseline is this issuer’s latest earlier reporting period of the same form that was filed before the current report. A previous 10-Q is a different quarter, not a year-over-year comparison. Amendments are excluded.
Compared 95 previous paragraphs and 92 current paragraphs.
32 unchanged; 31 reworded; 25 added; 31 removed; 1 previous and 4 current paragraphs rearranged.
Tables are not compared: 2 previous and 5 current tables excluded. Dates, whitespace, punctuation and numbering changes are ignored; changes to financial figures remain significant.
A changed paragraph is not evidence that risk increased or decreased. An unchanged paragraph does not establish that risk stayed the same.
Added paragraphs (25)
Current report
Our Portfolio and Development Plan Updates
Current report
In May 2025, we initiated our SKYLINE-UC Phase 2 platform trial evaluating SPY001, SPY002, SPY003, as well as pairwise combinations thereof (six active investigational agents in total), in patients with moderately to severely active UC. The trial consists of two parts:
Current report
•Part A: Open-label assessment of the safety and preliminary efficacy of a single dose level of each investigational monotherapy.
Current report
•Part B: Randomized and placebo-controlled assessment of the safety and efficacy of monotherapies and combinations, designed to provide dose-ranging data on monotherapies, proof-of-concept and contribution of components for combinations.
Current report
SKYLINE-UC is currently enrolling subjects into the SPY001 arm of Part A.
Current report
SKYWAY-RD Phase 2 Basket Trial in Rheumatic Diseases (RA, PsA, axSpA)
Current report
SKYWAY-RD is a planned Phase 2 randomized and placebo-controlled basket trial of SPY072 in patients with moderately to severely active RA, PsA, or axSpA. Trial initiation is expected in the third quarter of 2025 and consists of three sub-studies:
Current report
•RA sub-study: Double-blind, placebo-controlled safety and efficacy study of two dose levels of SPY072 at Week 12 with open-label follow-up through Week 36.
Current report
•PsA sub-study: Double-blind, placebo-controlled safety and efficacy study of a single dose level of SPY072 at Week 16 with open-label follow-up through Week 40.
Current report
•axSpA sub-study: Double-blind, placebo-controlled safety and efficacy study of a single dose level of SPY072 at Week 16 with open-label follow-up through Week 40.
Current report
SPY002 and SPY072 – anti-TL1A mAbs
Current report
SPY002 and SPY072 bind TL1A monomers and trimers and have subnanomolar potency in preclinical cellular assays. We initiated FIH Phase 1 trials for SPY002 and SPY072 in the fourth quarter of 2024. The Phase 1 trials were each double blind, placebo-controlled evaluations in healthy volunteers, consisting of five SAD cohorts. Each trial enrolled 40 healthy adult participants across the five SAD cohorts in the main portion of the study. The primary endpoint is safety, with PK and ADAs serving as secondary endpoints, and PD markers as exploratory endpoints. Additional cohorts may be added to the SPY002 and SPY072 Phase 1 studies, for example to evaluate PK in healthy volunteers of various ethnicities, to facilitate subsequent global clinical trials.
Current report
Phase 1 data were presented in June 2025, with up to 20-weeks of follow up. To date, SPY002 and SPY072 have demonstrated favorable safety profiles, meaningfully differentiated PK profiles supporting potential quarterly or twice annual maintenance dosing, and complete suppression of free TL1A through up to 20 weeks at single 100mg doses. Based on these interim results, in the third quarter of 2025, SPY002 is expected to advance to the SKYLINE-UC Phase 2 platform trial and SPY072 is expected to advance to the SKYWAY-RD Phase 2 basket trial.
Current report
Research and Development Expenses. Research and development expenses increased by $7.5 million, or 23%, to $40.1 million for the three months ended June 30, 2025, from $32.6 million for the three months ended June 30, 2024. The increase was primarily driven by higher clinical trial expenses and increased compensation costs, partially offset by lower early-stage R&D costs coupled with decreased intellectual property license and sub-licensing fees.
Current report
Gain on Sale of In-Process Research and Development Asset. During the three months ended June 30, 2025, the Company recognized a gain of $10.0 million for achieved milestones related to the 2023 sale of the global rights of the legacy Aeglea asset pegzilarginase to Immedica, driven by a favorable reimbursement decision for pegzilarginase in Europe. There was no similar gain or loss during the three months ended June 30, 2024.
Current report
Other expense, net. Other expense, net for the three months ended June 30, 2025 remained flat compared to the three months ended June 30, 2024. Changes in fair value of the CVR liability comprise the majority of Other expense, net.
Current report
Comparison of the Six Months Ended June 30, 2025 and 2024
Current report
*Percentage not meaningful
Current report
Research and Development Expenses. Research and development expenses increased by $14.2 million, or 21%, to $81.8 million for the six months ended June 30, 2025, from $67.6 million for the six months ended June 30, 2024. The increase was primarily driven by higher clinical development activities and increased compensation costs, partially offset by lower early-stage R&D costs coupled with decreased intellectual property license and sub-licensing fees.
Current report
External research and development expenses include costs associated with third parties contracted to conduct research and development activities on our behalf, including through Paragon, contract research organizations, contract manufacturing organizations, and third-party laboratories. For the six months ended June 30, 2025 and 2024, external research and development costs accounted for $63.9 million and $59.1 million, respectively. Preclinical expenses decreased primarily due to a reduction in early-stage R&D activities given our pipeline's advancement coupled with lower intellectual property license and sub-licensing fees. IBD expenses increased primarily due to an increase in clinical development costs related to ongoing or planned clinical trials partially offset by decreased manufacturing costs. Rheumatic diseases costs increased due to increases in manufacturing and clinical development costs. External stock-based compensation decreased due to our obligations ending under the Parapyre Option Obligation.
Current report
General and Administrative Expenses. General and administrative expenses decreased by $0.6 million, or 3%, to $23.7 million for the six months ended June 30, 2025, from $24.4 million for the six months ended June 30, 2024. The decrease was primarily due to legacy Aeglea employee and director separation costs in the prior period.
Current report
Gain on Sale of In-Process Research and Development Asset. During the six months ended June 30, 2025, the Company recognized a gain of $10.0 million for achieved milestones related to the 2023 sale of the global rights of the legacy Aeglea asset pegzilarginase to Immedica, driven by a favorable reimbursement decision for pegzilarginase in Europe. There was no similar gain or loss during the six months ended June 30, 2024.
Current report
Cash used in operating activities for the six months ended June 30, 2025 was $87.6 million and primarily reflected a net loss of $81.5 million coupled with net loss adjustments of a $10.0 million gain on sale of in-process-research and development and a $9.6 million decrease in net operating assets and liabilities driven by timing of payments to vendors, partially offset by stock-based compensation of $18.2 million.
Current report
Cash Provided By (Used in) Investing Activities
Current report
Cash provided by investing activities for the six months ended June 30, 2025 was $78.9 million and primarily consisted of $106.3 million in purchases of marketable securities, $7.0 million in proceeds from the sale of in-process research & development asset, partially offset by $178.2 million in maturities and sales of marketable securities.
Removed paragraphs (31)
Previous report
Our Portfolio
Previous report
Through the Asset Acquisition, we received the Option pursuant to the Paragon Agreement, and subsequently executed license agreements for our α4β7, TL1A, and IL-23 programs. As of the date of this Quarterly Report on Form 10-Q, we have exercised our Option with respect to and nominated development candidates for our SPY001, SPY002, and SPY003 programs. We executed license agreements with Paragon for SPY001 (the "SPY001 License Agreement") and SPY002 (the "SPY002 License Agreement") in the second quarter of 2024 and we executed a license agreement with Paragon for SPY003 (the "SPY003 License Agreement" and, together with the SPY001 License Agreement and the SPY002 License Agreement, the "License Agreements") in the fourth quarter of 2024. The SPY001 and SPY002 licenses are indication agnostic, and the SPY003 license is restricted to IBD. See the section titled “Paragon Agreement” in this Quarterly Report on Form 10-Q for more discussion about the Paragon Agreement and the License Agreements.
Previous report
SPY001 preclinical characterization studies were conducted in-house with support from third party vendors. SPY001 demonstrates similar potency and selectivity as synthesized vedolizumab in preclinicalin vitro models including surface plasmon residence (n=5 concentrations) and cellular adhesion assays (see Figure 1, n=6 replicates per group).
Previous report
•Safety (See Figure 2) - SPY001 was well tolerated across all dose groups (single doses of up to 1,000 mg and multiple doses of up to 600 mg) with a favorable safety profile. The most common treatment-emergent adverse events were headache and nasopharyngitis.
Previous report
•PK (See Figure 3) - SPY001 demonstrated a meaningfully differentiated PK profile relative to vedolizumab. SPY001 has a half-life estimate of ~80 days based on population PK modeling, more than three times that of vedolizumab's 25-day human half-life in a cross-trial comparison, supporting the potential for Q3M-Q6M SC maintenance dosing.
Previous report
•Pharmacodynamics ("PD") (see Figure 4) - saturation of occupancy of α4β7 receptors was observed with a single dose of 600 mg up to 32 weeks of follow up, which was the longest follow-up available at data cutoff.
Previous report
Based on these interim results, we plan to advance SPY001 to a Phase 2 clinical trial in UC patients in mid-2025.
Previous report
Figure 1. Potency and selectivity of SPY001 relative to synthesized vedolizumab in cellular assays (Data on file).
Previous report
Figure 2. Interim SPY001 Phase 1 safety data.
Previous report
Figure 3. Interim SPY001 simulated concentration-time profile compared to vedolizumab.
Previous report
Figure 4. Interim SPY001 pharmacodynamic data.
Previous report
SPY002 – anti-TL1A mAb
Previous report
SPY002 preclinical characterization studies were conducted in-house with support from third party vendors. Our extensive discovery campaign has identified two lead candidates which bind TL1A monomers and trimers and have subnanomolar potency in cellular assays (see Figure 5, n=4 replicates per group per study). The candidates also exhibited extended pharmacokinetic half-lives of greater than two to three-fold relative to synthesized competitor molecules in clinical development that do not incorporate half-life extending modifications, based on head-to-head preclinical studies in non-human primates ("NHPs") (see Figure 6, n=5 per group).
Previous report
The Company initiated two FIH trials in healthy volunteers in the fourth quarter of 2024, one for each of our SPY002 candidates, with interim safety and PK data from these trials expected in the second quarter of 2025. If successful, one or more SPY002 candidates will advance to Phase 2 clinical trials (UC and RA).
Previous report
Figure 5. Inhibition of TL1A induced TF-1 cell apoptosis (left) and IFNγ secretion in primary human whole blood 1 donor of 4 donors profiled (right) (Data on file. Duvakitug was not benchmarked in IFNγ secretion assay; Duvakitug, RO7790121, and tulisokibart are synthesized comparator antibodies).
Previous report
Figure 6. Pharmacokinetic concentration-time curves of SPY002 candidates compared to synthesized competing anti-TL1A molecules in non-human primates (Data on file. Group size was n=5 for SPY002 mAbs and tulisokibart at final endpoints for half-life determination; No RO7790121 detected after day 28. Duvakitug not compared in these models given low human half-life (7-10 days).
Previous report
Figure 7. Inhibition of IL-23 induced STAT3 phosphorylation in a human lymphoma cell line (DB) (left) and IL-23 induced IL-17 secretion in human peripheral blood mononuclear cells (right) by SPY003 and synthesized risankizumab (Data on file).
Previous report
Figure 8. Pharmacokinetic concentration-time curves of SPY003 candidate compared to synthesized risankizumab comparator in non-human primates (Data on file. Group size was n=4 in the NHP studies with n=4 and n=3 at the final timepoint for half-life determination for SPY003 and risankizumab, respectively).
Previous report
Figure 9. Combined inhibition of anti-TL1A and anti-ß7 (anti-α4β7 mouse surrogate) is superior to either monotherapy in mouse models of colitis.
Previous report
Figure 10. Coadministration of SPY001 and SPY002 demonstrates no drug-drug effects on exposure in NHPs.
Previous report
Figure 11. Combination of anti-ß7 (anti-α4β7 murine surrogate) and anti-IL-23 increases efficacy and PD in T-cell transfer colitis model.
Previous report
Figure 12. Combined inhibition of anti-IL-23 and anti-ß7 (anti-α4β7 mouse surrogate) is superior to either monotherapy in mouse TNBS models of colitis (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. vehicle (2-way ANOVA with Dunnett’s correction). N=8 per group).
Previous report
In March 2025, the Company presented additional preclinical data, demonstrating that combination therapy resulted in additive in vivo biological activity relative to either monotherapy in mouse TNBS model (Figure 14).
Previous report
Figure 13. Combination of anti-TL1A and anti-IL-23 offers superior inhibition of IL-17 release in vitro.
Previous report
Figure 14. Combined inhibition of anti-IL-23 and anti-TL1A is superior to either monotherapy in mouse TNBS model of colitis (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. vehicle (2-way ANOVA with Dunnett’s correction). N=8 per group.
Previous report
We plan to initiate in mid-2025 (i) a Phase 2 platform trial of our product candidates in IBD beginning with monotherapies in mid-2025 and subsequent planned addition of combination arms and (ii) a Phase 2 clinical trial of anti-TL1A in RA, each subject to regulatory feedback and with initial topline Phase 2 results expected to be received in 2026.
Previous report
Research and Development Expenses. Research and development expenses increased by $6.7 million, or 19%, to $41.6 million for the three months ended March 31, 2025, from $34.9 million for the three months ended March 31, 2024. The increase was primarily driven by $13.5 million and $5.3 million increases in clinical and preclinical development activities, respectively, a $4.7 million increase in compensation costs, and a $2.5 million increase in intellectual property license fees, partially offset by $17.1 million and $3.5 million decreases in antibody discovery costs and manufacturing costs, respectively.
Previous report
Cash used in operating activities for the three months ended March 31, 2025 was $41.0 million and reflected a net loss of $44.8 million coupled with $2.6 million in net accretion of discount on marketable securities and a $2.4 million non-cash gain from the decrease of the CVR liability fair value, partially offset by stock-based compensation of $8.9 million.
Previous report
Cash Used in Investing Activities
Previous report
Cash used in investing activities for the three months ended March 31, 2025 was $0.1 million.
Previous report
Cash provided by financing activities for the three months ended March 31, 2025 was $0.1 million.
Reworded paragraphs (31)
Previous wording
You should read the following discussion and analysis of our financial condition and results of operations in conjunction with our unaudited condensed consolidated financial statements and related notes included in Part I, Item 1 of this Quarterly Report on Form 10-Q for the quarterly period ended March 31, 2025 (this "Quarterly Report") as well as the audited consolidated financial statements and notes and Management’s Discussion and Analysis of Financial Condition and Results of Operations, included in our Annual Report on Form 10-K for the year ended December 31, 2024 (the "Annual Report") filed with the U.S. Securities and Exchange Commission (the "SEC") on February 27, 2025. This discussion and other parts of this Quarterly Report contain forward-looking statements that involve risks and uncertainties, such as statements regarding our expected results, outcomes, and the timing of these results and outcomes, plans, objectives, expectations and intentions. As a result of many factors, including those factors set forth in the “Risk Factors” section of this Quarterly Report, our actual results could differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis. As used in this report, unless the context suggests otherwise, “we”, “us”, “our”, “the Company,” or “Spyre” refers to Spyre Therapeutics, Inc. and its consolidated subsidiaries taken as a whole.
Current wording
You should read the following discussion and analysis of our financial condition and results of operations in conjunction with our unaudited condensed consolidated financial statements and related notes included in Part I, Item 1 of this Quarterly Report for the quarterly period ended June 30, 2025 (this "Quarterly Report") as well as the audited consolidated financial statements and notes and Management’s Discussion and Analysis of Financial Condition and Results of Operations, included in our Annual Report on Form 10-K for the year ended December 31, 2024 (the "Annual Report") filed with the U.S. Securities and Exchange Commission (the "SEC") on February 27, 2025. This discussion and other parts of this Quarterly Report contain forward-looking statements that involve risks and uncertainties, such as statements regarding our expected results, outcomes, and the timing of these results and outcomes, plans, objectives, expectations and intentions. As a result of many factors, including those factors set forth in the “Risk Factors” section of this Quarterly Report, our actual results could differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis. As used in this report, unless the context suggests otherwise, “we”, “us”, “our”, “the Company,” or “Spyre” refers to Spyre Therapeutics, Inc. and its consolidated subsidiaries taken as a whole.
Previous wording
Through the Asset Acquisition, we received the option to license certain intellectual property rights related to certain research programs (collectively, the "Option"). On July 12, 2023, we exercised the Option with respect to one of these research programs to be granted an exclusive license to all of Paragon's rights, title and interest in and to intellectual property rights, including inventions, patents, sequence information and results, under SPY001, our α4β7 integrin program, to develop and commercialize antibodies and products worldwide in all therapeutics disorders. We expect any patents pursued non-provisionally and that mature into issued patents to expire no earlier than 2044, subject to any disclaimers or extensions. On December 14, 2023, we exercised the Option under the Paragon Agreement to be granted an exclusive license to all of Paragon’s rights, title and interest in and to intellectual property rights, including inventions, patents, sequence information and results, under SPY002, our TL1A program, to develop and commercialize antibodies and products worldwide in all therapeutics disorders. We expect any patents pursued non-provisionally and that mature into issued patents to expire no earlier than 2044, subject to any disclaimers or extensions. On June 5, 2024, we exercised the Option under the Paragon Agreement to be granted an exclusive license to all of Paragon’s rights, title and interest in and to intellectual property rights, including inventions, patents, sequence information and results, under SPY003, our IL-23 program, to develop and commercialize antibodies and products worldwide solely in inflammatory bowel disease ("IBD") indications. We expect any patents pursued non-provisionally and that mature into issued patents to expire no earlier than 2045, subject to any disclaimers or extensions. The License Agreements pertaining to SPY001 and SPY002 between the Company and Paragon were executed in the second quarter of 2024, and the License Agreement pertaining to SPY003 was executed in October 2024 and subsequently amended and restated on February 24, 2025.
Current wording
Through the Asset Acquisition, we received the option to license certain intellectual property rights related to certain research programs (collectively, the "Option"). On July 12, 2023, we exercised the Option with respect to one of these research programs to be granted an exclusive license to all of Paragon's rights, title and interest in and to intellectual property rights, including inventions, patents, sequence information and results, under SPY001, our α4β7 integrin program, to develop and commercialize antibodies and products worldwide in all therapeutics disorders. We expect any patents pursued non-provisionally and that mature into issued patents to expire no earlier than 2044, subject to any disclaimers or extensions. On December 14, 2023, we exercised the Option under the Paragon Agreement to be granted an exclusive license to all of Paragon’s rights, title and interest in and to intellectual property rights, including inventions, patents, sequence information and results, under SPY002 (formerly SPY002-091) and SPY072 (formerly SPY002-072), our TL1A programs, to develop and commercialize antibodies and products worldwide in all therapeutics disorders. We expect any patents pursued non-provisionally and that mature into issued patents to expire no earlier than 2044, subject to any disclaimers or extensions. On June 5, 2024, we exercised the Option under the Paragon Agreement to be granted an exclusive license to all of Paragon’s rights, title and interest in and to intellectual property rights, including inventions, patents, sequence information and results, under SPY003, our IL-23 program, to develop and commercialize antibodies and products worldwide solely in inflammatory bowel disease ("IBD") indications. We expect any patents pursued non-provisionally and that mature into issued patents to expire no earlier than 2045, subject to any disclaimers or extensions. The license agreements pertaining to SPY001 (the "SPY001 License Agreement") and SPY002 and SPY072 (the "SPY002 and SPY072 License Agreement") between the Company and Paragon were executed in the second quarter of 2024, and the license agreement pertaining to SPY003 (the "SPY003 License Agreement" and, together with the SPY001 License Agreement and the SPY002 and SPY072 License Agreement, the "License Agreements") between the Company and Paragon was executed in October 2024 and subsequently amended and restated on February 24, 2025. See the section titled “Paragon Agreement” in this Quarterly Report for more discussion about the Paragon Agreement and the License Agreements.
Previous wording
Following the Asset Acquisition, we have significantly reshaped the business into a clinical stage biotechnology company focused on developing next generation therapeutics for patients living with IBD, including ulcerative colitis ("UC") and Crohn's disease ("CD"), and other immune-mediated diseases. Our portfolio of novel and proprietary monoclonal antibody product candidates has the potential to address unmet needs in IBD and rheumatoid arthritis ("RA") care by improving efficacy, safety, and/or dosing convenience relative to products currently available or product candidates in development. We have engineered our product candidates with the aim to bind potently and selectively to their target epitopes and to exhibit extended pharmacokinetic half-lives through modifications in the Fc domain, which modifications are designed to increase affinity to human FcRn and increase antibody recycling. We anticipate that half-life extension will enable less frequent administration as compared to marketed or development-stage mAbs that do not incorporate half-life extension modifications. In addition to the development of our product candidates as potential monotherapies, we plan to investigate combinations of our proprietary antibodies in nonclinical studies and clinical trials in order to evaluate whether combination therapy (co-administration or co-formulation of multiple monoclonal antibodies) can lead to greater efficacy, as compared to monotherapies in IBD. We intend to deliver our product candidates through convenient, infrequently self-administered, subcutaneous maintenance injections, although the specific delivery mechanism or technology has not been selected given our early stage.
Current wording
Following the Asset Acquisition, we have significantly reshaped the business into a clinical stage biotechnology company focused on developing next generation therapeutics for patients living with IBD, including ulcerative colitis ("UC") and Crohn's disease ("CD"), and rheumatic diseases ("RD"), including rheumatoid arthritis ("RA"), psoriatic arthritis ("PsA"), and axial spondyloarthritis ("axSpA"). Our portfolio of novel and proprietary monoclonal antibody product candidates has the potential to address unmet needs in IBD and RD care by improving efficacy, safety, and/or dosing convenience relative to products currently available or product candidates in development. We have engineered our product candidates with the aim to bind potently and selectively to their target epitopes and to exhibit extended pharmacokinetic ("PK") half-lives through modifications in the Fc domain, which modifications are designed to increase affinity to human FcRn and increase antibody recycling. We anticipate that half-life extension will enable less frequent administration as compared to marketed or development-stage mAbs that do not incorporate half-life extension modifications. In addition to the development of our product candidates as potential monotherapies, we plan to investigate combinations of our proprietary antibodies in nonclinical studies and clinical trials in order to evaluate whether combinations (co-administration or co-formulation of multiple monoclonal antibodies) can lead to greater efficacy, as compared to monotherapies in IBD. We intend to deliver our product candidates through convenient, infrequently self-administered, subcutaneous maintenance injections, although the specific delivery mechanism or technology has not been selected given our early stage.
Previous wording
We are advancing a pipeline of monoclonal antibodies (“mAbs”) for the treatment of IBD and other immune-mediated diseases. The following table summarizes our programs and strategy:
Current wording
We are advancing a pipeline of monoclonal antibodies (“mAbs”) for the treatment of IBD and RD. The following table summarizes our pipeline and development strategy, including our initiated SKYLINE-UC Phase 2 platform study evaluating SPY001, SPY002, SPY003, and pairwise combinations thereof in patients with moderately to severely active UC and our planned SKYWAY-RD basket study evaluating SPY072 in three rheumatic diseases: RA, PsA, and axSpA.
Previous wording
Phase 2 Platform Trial in UC and Phase 2 Trial in RA
Current wording
SKYLINE-UC Phase 2 Platform Trial in UC
Previous wording
The Company initiated a first-in-human ("FIH") Phase 1 trial for SPY001 in June 2024. The SPY001 Phase 1 trial is a double blind, placebo-controlled trial in healthy volunteers and consists of a single-ascending dose ("SAD") component and a multi-ascending dose ("MAD") component. The trial design includes enrolling 56 healthy adult participants into five SAD cohorts and two MAD cohorts in the main portion of the study. The primary endpoint is safety, with pharmacokinetics ("PK") and anti-drug antibodies ("ADA") serving as secondary endpoints. Additional cohorts have been added to the study to evaluate pharmacokinetics in healthy volunteers of various ethnicities to facilitate subsequent global clinical trials. Trial enrollment is now complete.
Current wording
SPY001 demonstrates similar potency and selectivity as synthesized vedolizumab in preclinicalin vitro models including surface plasmon residence and cellular adhesion assays. We initiated a first-in-human ("FIH") Phase 1 trial for SPY001 in June 2024. The SPY001 Phase 1 trial is a double blind, placebo-controlled trial in healthy volunteers and consists of a single-ascending dose ("SAD") component and a multi-ascending dose ("MAD") component. The trial design includes enrolling 56 healthy adult participants into five SAD cohorts and two MAD cohorts in the main portion of the study. The primary endpoint is safety, with PK and anti-drug antibodies ("ADA") serving as secondary endpoints. Additional cohorts have been added to the study to evaluate PK in healthy volunteers of various ethnicities to facilitate subsequent global clinical trials. Trial enrollment is now complete.
Previous wording
Interim results were initially presented in November 2024, with additional data presented in May 2025 with up to eight months of follow up. Findings from the interim SAD and MAD portions of the Phase 1 trial were as follows:
Current wording
Interim results were initially presented in November 2024, with additional data presented in May 2025 with up to eight months of follow up. To date, SPY001 has demonstrated a favorable safety profile across all dose groups, a meaningfully differentiated PK profile supporting potential quarterly or twice annual maintenance dosing, and rapid and complete saturation of α4β7 receptors beyond six months with a single dose of 600mg. Based on these results, SPY001 was advanced into the SKYLINE-UC Phase 2 platform clinical trial, which initiated in May 2025.
Previous wording
For our SPY002 program, we nominated two highly potent, highly selective, and fully human mAb candidates designed to bind to tumor necrosis factor-like ligand 1A (“TL1A”), both of which are being developed for the treatment of IBD (UC and CD) and RA. TL1A is a protein that plays a role in regulating the immune system and is elevated in the gut tissue of individuals with IBD and synovial tissue of individuals with RA. TL1A interacts with its receptor, death receptor 3 (“DR3”), which is expressed in various immune cells, including T cells. This interaction triggers signaling pathways that contribute to inflammation and immune system activation, leading to IBD or RA symptomology. The SPY002 candidates have been designed to block the interaction between TL1A and DR3, and thereby inhibit the downstream signaling events and dampen the inflammatory response. By neutralizing TL1A, we believe the SPY002 candidates have the potential to modulate the immune response in IBD and RA patients, potentially reducing disease activity.
Current wording
For our anti-TL1A program, we nominated two highly potent, highly selective, and fully human mAb candidates designed to bind to tumor necrosis factor-like ligand 1A (“TL1A”). SPY002 (formerly SPY002-091) is being developed for the treatment of IBD (UC and CD) and SPY072 (formerly SPY002-072) is being developed for the treatment of RD. TL1A is a protein that plays a role in regulating the immune system and is elevated in the gut tissue of individuals with IBD and serum or synovial tissue of individuals with RA, PsA, and axSpA. TL1A interacts with its receptor, death receptor 3 (“DR3”), which is expressed in various immune cells, including T cells and fibroblast-like synoviocytes. This interaction triggers signaling pathways that contribute to inflammation and joint injury in RD, leading to symptomology, such as pain and swelling. SPY002 and SPY072 have been designed to block the interaction between TL1A and DR3, and thereby inhibit the downstream signaling events to dampen the inflammatory response. By neutralizing TL1A, we believe that SPY002 and SPY072 have the potential to modulate the immune response in IBD and RD patients, potentially reducing disease activity.
Previous wording
SPY003 preclinical characterization studies were conducted in-house with support from third party vendors. Our extensive discovery campaign has identified a lead candidate which binds to the p19 subunit of IL-23 with subnanomolar potency in cellular assays (see Figure 7, n=2 and n=3 for pSTAT assay and IL-17 assay, respectively). The development candidate also exhibited extended pharmacokinetic half-life of greater than three-fold relative to a synthesized risankizumab comparator that does not incorporate half-life extending modifications, based on head-to-head preclinical studies in NHPs (see Figure 8, n=4 per group with n=4 and n=3 at the final timepoint for half-life determination for SPY003 and risankizumab, respectively).
Current wording
SPY003 binds to the p19 subunit of IL-23 with subnanomolar potency in cellular assays. SPY003 also exhibited extended PK half-life of greater than three-fold relative to a synthesized risankizumab comparator that does not incorporate half-life extending modifications, based on head-to-head preclinical studies in non-human primates ("NHPs").
Previous wording
The Company initiated a FIH trial in healthy volunteers in March 2025, with interim safety and PK data from this trial expected in the second half of 2025. If successful, SPY003 will advance to Phase 2 clinical trials.
Current wording
We initiated a FIH trial in healthy volunteers in March 2025, with interim safety and PK data from this trial expected in the fourth quarter of 2025. If successful, SPY003 will advance to the SKYLINE-UC Phase 2 platform trial.
Previous wording
SPY120 combines SPY001 (anti-α4β7) and SPY002 (anti-TL1A) antibodies, pairing two mechanisms studied in third-party clinical trials targeting non-overlapping sites of action. We are currently evaluating SPY120 in nonclinical studies, and have initiated combination toxicology studies. Subject to regulatory feedback, we intend to initiate clinical trials in 2025 that will include SPY120.
Current wording
SPY120 combines SPY001 (anti-α4β7) and SPY002 (anti-TL1A) antibodies, pairing two mechanisms studied in third-party clinical trials targeting non-overlapping sites of action. We are currently evaluating SPY120 in nonclinical studies, and have initiated combination toxicology studies. Subject to regulatory feedback, we intend to include SPY120 in the SKYLINE-UC Phase 2 platform trial.
Previous wording
In February and May 2025, the Company presented new preclinical data demonstrating that combination therapy resulted in additive or greater than additive in vivo biological activity relative to either monotherapy in mouse hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS) and anti-CD40 colitis models (Figure 9). In addition, coadministration of SPY001 and SPY002 in NHPs demonstrated no drug effects on PK (Figure 10).
Current wording
In February and May 2025, we presented new preclinical data demonstrating that combinations resulted in additive or greater than additive in vivo biological activity relative to either monotherapy in mouse hapten reagent 2,4,6-trinitrobenzene sulfonic acid ("TNBS") and anti-CD40 colitis models. In addition, coadministration of SPY001 and SPY002 in NHPs demonstrated no drug effects on PK.
Previous wording
SPY130 combines SPY001 (anti-α4β7) and SPY003 (anti-IL-23) antibodies, pairing two commercially validated mechanisms targeting non-overlapping sites of action. We are currently evaluating SPY130 in nonclinical studies and initiated combination toxicology studies in 2024. Subject to regulatory feedback, we intend to initiate clinical trials in 2025 that will include SPY130.
Current wording
SPY130 combines SPY001 (anti-α4β7) and SPY003 (anti-IL-23) antibodies, pairing two commercially validated mechanisms targeting non-overlapping sites of action. We are currently evaluating SPY130 in nonclinical studies and initiated combination toxicology studies in 2024. Subject to regulatory feedback, we intend to include SPY130 in the SKYLINE-UC Phase 2 platform trial.
Previous wording
In October 2024, the Company presented new preclinical data, demonstrating in a T-cell transfer model of IBD, that combination therapy with anti-IL-23 and anti-α4ß7 improved body weight and reduced colonic CD4+ infiltration and IL-17 levels relative to monotherapy (Figure 11).
Current wording
In October 2024, we presented new preclinical data, demonstrating in a T-cell transfer model of IBD, that combinations with anti-IL-23 and anti-α4ß7 improved body weight and reduced colonic CD4+ infiltration and IL-17 levels relative to monotherapy. In March 2025, we presented additional preclinical data, demonstrating that combinations resulted in additive or greater than additive in vivo biological activity relative to either monotherapy in mouse TNBS model.
Previous wording
SPY230 combines SPY002 (anti-TL1A) and SPY003 (anti-IL-23) antibodies, pairing two complementary mechanisms of action with potential to address overlapping and non-overlapping triggers of inflammation. We are currently evaluating SPY230 in nonclinical studies and initiated combination toxicology studies in 2024. Subject to regulatory feedback, we intend to initiate clinical trials in 2025 that will include SPY230.
Current wording
SPY230 combines SPY002 (anti-TL1A) and SPY003 (anti-IL-23) antibodies, pairing two complementary mechanisms of action with potential to address overlapping and non-overlapping triggers of inflammation. We are currently evaluating SPY230 in nonclinical studies and initiated combination toxicology studies in 2024. Subject to regulatory feedback, we intend to include SPY230 in the SKYLINE-UC Phase 2 platform trial.
Previous wording
In October 2024, the Company presented new preclinical data, demonstrating that anti-IL-23 and anti-TL1A have a synergistic effect on promoting IL-17 secretion from human and mouse cells, and that the combination of anti-IL-23 and anti-TL1A suppressed IL-17 secretion more effectively than either agent alone (Figure 13).
Current wording
In October 2024, we presented new preclinical data, demonstrating that anti-IL-23 and anti-TL1A have a synergistic effect on promoting IL-17 secretion from human and mouse cells, and that the combination of anti-IL-23 and anti-TL1A suppressed IL-17 secretion more effectively than either agent alone. In March 2025, we presented additional preclinical data, demonstrating that combinations resulted in additive in vivo biological activity relative to either monotherapy in mouse TNBS model.
Previous wording
On July 12, 2023, December 14, 2023 and June 5, 2024, we exercised our Option available under the Paragon Agreement with respect to the SPY001, SPY002 and SPY003 research programs, respectively. In May 2024, we signed license agreements with Paragon for rights to royalty-bearing, world-wide, exclusive licenses to develop, manufacture, commercialize or otherwise exploit certain antibodies and products targeting ɑ4β7 integrin (SPY001 program) and TL1A (SPY002 program) and, in October 2024, we signed a license agreement for rights to a royalty-bearing, world-wide, exclusive license to develop, manufacture, commercialize or otherwise exploit certain antibodies and products targeting IL-23 (SPY003 program) in the field of IBD. The SPY003 License Agreement was subsequently amended and restated in February 2025 to, among other things, clarify each party's rights and obligations with respect to license exclusivity and patent prosecution.
Current wording
On July 12, 2023, December 14, 2023 and June 5, 2024, we exercised our Option available under the Paragon Agreement with respect to the SPY001, SPY002, SPY072 and SPY003 research programs, respectively. In May 2024, we signed license agreements with Paragon for rights to royalty-bearing, world-wide, exclusive licenses to develop, manufacture, commercialize or otherwise exploit certain antibodies and products targeting ɑ4β7 integrin (SPY001 program) and TL1A (SPY002 and SPY072 programs) and, in October 2024, we signed a license agreement for rights to a royalty-bearing, world-wide, exclusive license to develop, manufacture, commercialize or otherwise exploit certain antibodies and products targeting IL-23 (SPY003 program) in the field of IBD. The SPY003 License Agreement was subsequently amended and restated in February 2025 to, among other things, clarify each party's rights and obligations with respect to license exclusivity and patent prosecution.
Previous wording
Under the terms of each License Agreement, we are obligated to pay Paragon up to $22.0 million upon the achievement of specific development, regulatory and clinical milestones for the first product under each agreement, respectively, that achieves such specified milestones, including a milestone payment of $3 million upon the first dosing of a human patient in a Phase 2 trial. With respect to the SPY002 License Agreement only, on a product by product basis, we are obligated to pay sublicensing fees of up to approximately $20 million upon the achievement of mostly commercial milestones.
Current wording
Under the terms of each License Agreement, we are obligated to pay Paragon up to $22.0 million upon the achievement of specific development, regulatory and clinical milestones for the first product under each agreement, respectively, that achieves such specified milestones, including a milestone payment of $3 million upon the first dosing of a human patient in a Phase 2 trial. With respect to the SPY002 and SPY072 License Agreement only, on a product by product basis, we are obligated to pay sublicensing fees of up to approximately $20 million upon the achievement of mostly commercial milestones.
Previous wording
External research and development expenses include costs associated with third parties contracted to conduct research and development activities on behalf of the Company, including through Paragon, CROs, CMOs, and third-party laboratories. For the three months ended March 31, 2025 and 2024, external research and development costs accounted for $33.5 million and $31.3 million, respectively. The increase was primarily due to increased clinical and preclinical development activities, intellectual property license fees, partially offset by decreases in antibody discovery and manufacturing costs associated with our pipeline candidates as described above.
Current wording
External research and development expenses include costs associated with third parties contracted to conduct research and development activities on our behalf, including through Paragon, contract research organizations ("CROs"), contract manufacturing organizations ("CMOs"), and third-party laboratories. For the three months ended June 30, 2025 and 2024, external research and development costs accounted for $30.4 million and $27.7 million, respectively. Preclinical expenses decreased primarily due to a reduction in early-stage R&D activities given our pipeline's advancement coupled with lower intellectual property license and sub-licensing fees. IBD expenses increased primarily due to an increase in clinical development activities related to ongoing or planned clinical trials partially offset by lower license and sub-licensing fees as well as lower manufacturing costs. Rheumatic diseases costs increased due to increases in manufacturing and clinical development costs. External stock-based compensation decreased due to our obligations ending under the Parapyre Option Obligation.
Previous wording
Internal research and development expenses include compensation and related costs associated with our research and development employees. For the three months ended March 31, 2025 and 2024, internal research and development costs accounted for $8.1 million and $3.6 million, respectively. The increase was primarily driven by an increase in research and development headcount.
Current wording
Internal research and development expenses include compensation and related costs associated with our research and development employees. For the three months ended June 30, 2025 and 2024, internal research and development costs accounted for $9.8 million and $4.9 million, respectively. The increase was primarily driven by an increase in research and development headcount.
Previous wording
General and Administrative Expenses. General and administrative expenses decreased by $0.9 million, or 7%, to $11.9 million for the three months ended March 31, 2025, from $12.8 million for the three months ended March 31, 2024. The decrease was primarily attributable to a $1.6 million decrease in stock-based compensation, partially offset by a $0.8 million increase in professional services fees.
Current wording
General and Administrative Expenses. General and administrative expenses increased by $0.3 million, or 2%, to $11.8 million for the three months ended June 30, 2025, from $11.5 million for the three months ended June 30, 2024. The increase was primarily attributable to an increase in compensation.
Previous wording
Interest Income. Interest income was $6.5 million and $4.4 million for the three months ended March 31, 2025 and 2024, respectively. The increase was primarily due to higher investment balances.
Current wording
Interest Income. Interest income was $12.4 million and $10.4 million for the six months ended June 30, 2025 and 2024, respectively. The increase was primarily due to higher investment balances.
Previous wording
Other income (expense), net. Other income (expense), net for the three months ended March 31, 2025 increased by $2.8 million versus the three months ended March 31, 2024 primarily driven by a $2.4 million decrease in fair value of the CVR liability during the current period compared to a $0.4 million increase in fair value of the contingent right liability during the prior period.
Current wording
Other income, net. Other income, net for the six months ended June 30, 2025 increased by $2.7 million versus the six months ended June 30, 2024 primarily driven by changes in the fair value of the CVR liability.
Previous wording
Since our inception and through March 31, 2025, we have funded our operations by raising an aggregate of approximately $1.3 billion of gross proceeds from the sale and issuance of convertible preferred stock and common stock, pre-funded warrants, the collection of grant proceeds, and the licensing of our product rights for commercialization of pegzilarginase in Europe and certain countries in the Middle East. As of March 31, 2025, we had an accumulated deficit of $1.0 billion.
Current wording
Since our inception and through June 30, 2025, we have funded our operations by raising an aggregate of approximately $1.3 billion of gross proceeds from the sale and issuance of convertible preferred stock and common stock, pre-funded warrants, the collection of grant proceeds, and the licensing of our product rights for commercialization of pegzilarginase in Europe and certain countries in the Middle East. As of June 30, 2025, we had an accumulated deficit of $1.1 billion.
Previous wording
Our primary use of cash is to fund the development of our product candidates, and advance our pipeline. This includes both the research and development costs and the general and administrative expenses required to support those operations. Since we are a clinical stage biotechnology company, we have incurred significant operating losses since our inception and we anticipate such losses, in absolute dollar terms, to increase as we continue to pursue clinical development of our product candidates, prepare for the potential commercialization of our product candidates, and expand our development efforts in our pipeline of nonclinical candidates. Based on current operating plans, we have sufficient resources to fund operations for at least one year from the issuance date of the financial statements included in this Quarterly Report with existing cash, cash equivalents, and marketable securities. We will need to secure additional financing in the future to fund additional research and development, and before a commercial drug can be produced, marketed and sold. If the Company is unable to obtain additional financing or generate license or product revenue, the lack of liquidity could have a material adverse effect on the Company.
Current wording
Our primary use of cash is to fund the development of our product candidates, and advance our pipeline. This includes both the research and development costs and the general and administrative expenses required to support those operations. Since we are a clinical stage biotechnology company, we have incurred significant operating losses since our inception and we anticipate such losses, in absolute dollar terms, to increase as we continue to pursue clinical development of our product candidates, prepare for the potential commercialization of our product candidates, and expand our development efforts in our pipeline of nonclinical candidates. Based on current operating plans, we have sufficient resources to fund operations for at least one year from the issuance date of the financial statements included in this Quarterly Report with existing cash, cash equivalents, and marketable securities. We will need to secure additional financing in the future to fund additional research and development, and before a commercial drug can be produced, marketed and sold. If we are unable to obtain additional financing or generate license or product revenue, the lack of liquidity could have a material adverse effect on us.
Previous wording
In September 2024 and December 2024, we sold an aggregate of 777,432 shares of common stock under an ATM offering program at an average price per share of $26.935 resulting in net proceeds of approximately $20.5 million after deducting approximately $0.4 million of sales agent commissions and other offering costs.
Current wording
In September 2024 and December 2024, we sold an aggregate of 777,432 shares of common stock under an ATM offering program resulting in net proceeds of approximately $20.5 million after deducting sales agent commissions and other offering costs.
Previous wording
Cash used in operating activities for the three months ended March 31, 2024 was $28.5 million and reflected a net loss of $43.9 million and $2.4 million in net accretion of discount on marketable securities, partially offset by stock-based compensation of $13.8 million and a $3.5 million decrease in net operating assets and liabilities driven by timing of payments.
Current wording
Cash used in operating activities for the six months ended June 30, 2024 was $90.8 million and reflected a net loss of $82.7 million, coupled with net loss adjustments of a $25.7 million decrease in net operating assets and liabilities driven by timing of payments to vendors and $6.0 million in net accretion of discount on marketable securities, partially offset by stock-based compensation of $22.5 million.
Previous wording
Cash used in investing activities for the three months ended March 31, 2024, was $105.0 million and primarily consisted of $152.7 million in purchases of marketable securities, partially offset by $47.8 million in maturities and sales of marketable securities.
Current wording
Cash used in investing activities for the six months ended June 30, 2024, was $225.5 million and primarily consisted of $331.1 million in purchases of marketable securities, partially offset by $105.6 million in maturities and sales of marketable securities.
Previous wording
Cash provided by financing activities for the three months ended March 31, 2024, was $172.2 million, which primarily consisted of the net proceeds from the issuance of the Series B Preferred Stock in the March 2024 PIPE of $169.2 million and $4.4 million from proceeds from stock option exercises and sales of common stock under our Employee Stock Purchase Plan.
Current wording
Cash provided by financing activities for the six months ended June 30, 2024, was $172.5 million, which primarily consisted of the net proceeds from the issuance of the Series B Preferred Stock in the March 2024 PIPE of $169.1 million and $4.9 million from proceeds from stock option exercises and sales of common stock under our Employee Stock Purchase Plan.
Previous wording
Through the Asset Acquisition, we received the Option to license certain intellectual property rights related to certain research programs. The exercise of the Option allows for us to enter into an exclusive license agreement with Paragon for the respective research program. Thus far we have exercised the Option and entered into license agreements with respect to SPY001, SPY002, and SPY003. Under the terms of each License Agreement, we are obligated to pay Paragon up to $22.0 million based on specific development, regulatory and clinical milestones for the first product under each agreement. As of March 31, 2025, we have incurred a total of $12.0 million of milestone fees out of a total maximum of $66.0 million in potential milestone fees across all License Agreements. As of March 31, 2025 $2.5 million of milestone fees remain outstanding and payable. With respect to the SPY002 License Agreement only, on a product by product basis, we are obligated to pay sublicensing fees of up to approximately $20 million upon the achievement of mostly commercial milestones. As of March 31, 2025 we have incurred $0.7 million of sublicensing fees of which nil remain outstanding and payable.
Current wording
Through the Asset Acquisition, we received the Option to license certain intellectual property rights related to certain research programs. The exercise of the Option allows for us to enter into an exclusive license agreement with Paragon for the respective research program. Thus far we have exercised the Option and entered into license agreements with respect to SPY001, SPY002, SPY072 and SPY003. Under the terms of each License Agreement, we are obligated to pay Paragon up to $22.0 million based on specific development, regulatory and clinical milestones for the first product under each agreement. As of June 30, 2025, we have incurred a total of $12.0 million of milestone fees out of a total maximum of $66.0 million in potential milestone fees across all License Agreements. As of June 30, 2025 no milestone fees remain outstanding and payable. With respect to the SPY002 and SPY072 License Agreement only, on a product by product basis, we are obligated to pay sublicensing fees of up to approximately $20 million upon the achievement of mostly commercial milestones. As of June 30, 2025 we have incurred $0.7 million of sublicensing fees of which nil remain outstanding and payable.
Previous wording
There were no recent accounting pronouncements that have had a material effect on the Company’s financial position or results of operations.
Current wording
There were no recent adopted accounting pronouncements that have had a material effect on our financial position or results of operations.
Rearranged current paragraphs (4)
Current report — wording carried from elsewhere
Interest Income. Interest income was $5.9 million for both the three months ended June 30, 2025 and 2024, respectively.
Current report — wording carried from elsewhere
The following table summarizes our results of operations for the six months ended June 30, 2025 and 2024, together with the changes in those items in dollars and as a percentage:
Current report — wording carried from elsewhere
Internal research and development expenses include compensation and related costs associated with our research and development employees. For the six months ended June 30, 2025 and 2024, internal research and development costs accounted for $17.9 million and $8.5 million, respectively. The increase was primarily driven by an increase in research and development headcount.
Current report — wording carried from elsewhere
Cash provided by financing activities for the six months ended June 30, 2025 was $0.9 million, which primarily consisted of proceeds from stock option exercises and sales of common stock under our Employee Stock Purchase Plan.
Rearranged previous paragraphs (1)
Previous report — wording carried elsewhere
In March 2025, the Company presented additional preclinical data, demonstrating that combination therapy resulted in additive or greater than additive in vivo biological activity relative to either monotherapy in mouse TNBS model (Figure 12).