Phase 2 Study to Assess the Efficacy and Safety of SPY002-072 in Adults with Moderately to Severely Active Rheumatologic Disease

This Phase 2 study comprises three distinct substudies evaluating the investigational agent SPY072 in adults with moderately to severely active rheumatologic diseases. The primary objective of the rheumatoid arthritis substudy is to assess the efficacy of SPY072 compared with placebo in reducing disease activity as measured by DAS28-CRP at Week 12. The primary objective of the axial spondyloarthritis substudy is to evaluate the efficacy of SPY072 compared with placebo in reducing disease activity as assessed by ASDAS at Week 16. The primary objective of the psoriatic arthritis substudy is to determine the efficacy of SPY072 compared with placebo in reducing disease activity as measured by ACR20 at Week 16. These primary endpoints are clinically relevant as they represent validated composite measures of disease activity that reflect meaningful improvements in inflammatory arthropathies and axial disease manifestations.

The secondary objectives across all three substudies include:

• Assessment of disease activity using alternative validated measures: ACR20 response at Week 12 in the rheumatoid arthritis substudy, ASAS40 response at Week 16 in the axial spondyloarthritis substudy, and DAPSA at Week 16 in the psoriatic arthritis substudy

• Evaluation of the pharmacokinetic profile of SPY072 in each disease population

• Assessment of the immunogenicity of SPY072 across all substudies

• Evaluation of the safety and tolerability profile of SPY072 in each rheumatologic disease cohort

The clinical trial enrolled a total of **183 participants** diagnosed with moderately to severely active **rheumatologic disease**, specifically including **rheumatoid arthritis** (RA), **axial spondyloarthritis** (axSpA), and **psoriatic arthritis** (PsA). The study population comprised both **male and female subjects** categorized as **adults** and **elderly participants**. The trial was designed for **patients** with documented diagnoses of their respective conditions for at least 6 months prior to screening. For the RA substudy, participants were required to meet the 2010 ACR/European League Against Rheumatism classification criteria and demonstrate moderate-to-severely active disease with at least 4 swollen joints and 4 tender joints based on a 28 joint count. The axSpA substudy included individuals with disease onset before age 45 years who met either the modified New York criteria or the 2009 ASAS classification criteria for non-radiographic axSpA, with a Bath Ankylosing Spondylitis Disease Activity Index score of at least 4 and back pain score of at least 4. The PsA substudy required participants to meet the Classification Criteria for PsA with at least 3 tender joints out of 68 and 3 swollen joints out of 66. All participants across substudies were required to have elevated **high-sensitivity C-reactive protein** (hsCRP) levels above the upper limit of normal at screening, indicating active inflammatory disease. Additional criteria included documentation of specific serological markers or radiographic findings relevant to each condition, and for the axSpA substudy, evidence of inadequate response to previous treatments with NSAIDs or biologic/targeted synthetic DMARDs.

This is a **Phase 2** clinical trial designed to evaluate the efficacy and safety of **SPY072** compared with **placebo** in adult participants with moderately to severely active **rheumatologic disease**. The study employs a **randomized**, **placebo-controlled** design and consists of three parallel substudies focusing on distinct rheumatologic conditions: **rheumatoid arthritis** (RA), **axial spondyloarthritis** (axSpA), and **psoriatic arthritis** (PsA). The investigational medicinal product SPY072 is administered as a **solution for injection** via **subcutaneous injection**, with a maximum treatment period of 40 weeks. The placebo comparator is SPYPBO-101, which matches the active treatment in appearance and administration route.

The primary objective of the RA substudy is to assess the efficacy of SPY072 in reducing disease activity as measured by the change from baseline in **DAS28-CRP** (Disease Activity Score 28 using C-reactive protein) at Week 12. For the axSpA substudy, the primary objective is to evaluate the change from baseline in **ASDAS** (Ankylosing Spondylitis Disease Activity Score) at Week 16. In the PsA substudy, the primary endpoint is the proportion of participants achieving an **ACR20** (American College of Rheumatology 20% improvement) response at Week 16. Secondary endpoints across all substudies include additional measures of disease activity, **pharmacokinetic** (PK) concentration assessments, the proportion of participants developing **anti-drug antibodies** (ADA), and the incidence of **treatment-emergent adverse events** (TEAEs), **serious adverse events** (SAEs), **adverse events of special interest** (AESIs), and adverse events leading to investigational product discontinuation.

Principal inclusion criteria require participants to have documented diagnoses of their respective rheumatologic conditions for at least 6 months prior to screening. For the RA substudy, participants must meet the 2010 ACR/European League Against Rheumatism classification criteria and demonstrate moderate-to-severely active disease defined by at least 4 swollen joints and at least 4 tender joints based on a 28-joint count at both screening and Day 1. The axSpA substudy requires participants to meet either the modified New York criteria for axSpA or the 2009 ASAS classification criteria for non-radiographic axSpA, with a **Bath Ankylosing Spondylitis Disease Activity Index** (BASDAI) score of at least 4 and back pain score of at least 4 at screening and Day 1. The PsA substudy requires participants to meet the Classification Criteria for PsA and have at least 3 tender joints out of 68 and at least 3 swollen joints out of 66 on Day 1. All substudies require **high-sensitivity C-reactive protein** (hsCRP) levels greater than the upper limit of normal at screening. Additional substudy-specific criteria include positive rheumatoid factor or anti-citrullinated peptide antibodies or radiographic evidence of bony erosions for RA participants, evidence of inadequate response to NSAIDs or prior biologic/targeted synthetic DMARDs for axSpA participants, and at least one active plaque psoriasis lesion or documented history of psoriasis for PsA participants.

The trial is expected to commence recruitment in December 2025 and conclude in March 2028, representing an overall trial duration of approximately 27 months. Participant involvement varies by substudy, with RA participants followed through Week 12 for primary efficacy assessments and axSpA and PsA participants followed through Week 16. All participants continue to be monitored through the end of the study for safety assessments. The study involves a screening visit to determine eligibility, a baseline visit on Day 1 for randomization and first dose administration, regular follow-up visits for efficacy and safety assessments at predetermined intervals, and an end-of-study visit. Participants may be withdrawn early from the study due to adverse events, lack of efficacy, withdrawal of consent, protocol violations, or investigator discretion. Safety monitoring includes assessment of adverse events, laboratory parameters, and immunogenicity throughout the treatment period and follow-up phase.

The experimental medication **SPY072** is formulated as a **solution for injection** containing the active substance SPY072, which is classified as a protein-based therapeutic agent. The investigational product is administered via **subcutaneous injection**. The maximum treatment period specified for SPY072 is 40 weeks. SPY072 is manufactured by Spyre Therapeutics Inc. and carries the sponsor product code SPY002-072. The dosing regimen, specific dose amounts, and administration frequency for SPY072 will be determined according to the study protocol design for the evaluation of efficacy and safety in participants with moderately to severely active rheumatologic disease, including **rheumatoid arthritis**, **axial spondyloarthritis**, and **psoriatic arthritis**.

The study includes a **placebo** comparator designated as SPYPBO-101 Placebo to SPY072. This placebo formulation is designed to match the experimental medication to maintain blinding integrity throughout the clinical trial. The placebo serves as the control treatment against which the efficacy and safety of SPY072 will be compared. Participants randomized to the placebo arm will receive injections that are identical in appearance and administration route to the active treatment, ensuring appropriate comparison of outcomes between treatment groups.

Efficacy will be assessed through distinct primary endpoints specific to each rheumatologic disease substudy. In the **rheumatoid arthritis** substudy, the primary efficacy parameter is the change from baseline in DAS28-CRP at Week 12. In the **axial spondyloarthritis** substudy, efficacy will be evaluated by the change in ASDAS from baseline to Week 16. In the **psoriatic arthritis** substudy, the primary endpoint is the proportion of participants who achieve an ACR20 response at Week 16.

Secondary efficacy endpoints include additional disease activity measures for each substudy. For the rheumatoid arthritis substudy, the proportion of participants achieving an ACR20 response at Week 12 will be assessed. In the axial spondyloarthritis substudy, the proportion of participants achieving an ASAS40 response at Week 16 will be evaluated. The psoriatic arthritis substudy will measure the change in DAPSA from baseline to Week 16. These endpoints will provide comprehensive evaluation of treatment efficacy across multiple validated disease activity measures and response criteria specific to each rheumatologic condition.