How Image Analysis Group (IAG) Supported SynAct Pharma’s Resomelagon (AP1189) Phase 2b EXPAND Program

In the Phase 2b EXPAND study, SynAct evaluated whether 100 mg once-daily resomelagon plus methotrexate could outperform methotrexate alone in treatment-naïve patients with severely active RA (CDAI > 22). The headline ACR20 readout did not separate the arms, 54.7% for resomelagon versus 55.7% for placebo driven in part by an unusually high placebo response and between-site variability concentrated in the subjective components of ACR (patient and investigator VAS, HAQ) (SynAct webcast, Sep 2023).

Reduction in tender and swollen joint counts, the objective components… favoured resomelagon and tracked with what had been seen in the earlier Phase 2a BEGIN study, where 100 mg resomelagon delivered a statistically significant 65% greater mean reduction in CDAI versus placebo at four weeks (SynAct BEGIN study page). The question for SynAct therefore became: can objective, quantitative imaging cut through the noise of subjective clinical scoring and reveal the underlying biology of resolution?

That is precisely the question DEMRIQ was built to answer.

In the pre-specified CRP-elevated population (baseline CRP > 3 mg/L), the population in which resomelagon delivered a 70.6% ACR20 versus 54.3% on placebo, the MRI sub-study (n = 23 resomelagon, n = 18 placebo) demonstrated (SynAct Pharma announcement, Oct 2023):

In the same elevated-CRP cohort, C4M (a marker of synovial collagen 4 degradation) was significantly reduced under resomelagon but unchanged under placebo, biologically corroborating the imaging signal (SynAct Pharma announcement, Oct 2023).

In other words, DEMRIQ recovered a coherent, biology-aligned treatment signal in the very subgroup where ACR20 separation was also seen, even though the overall ACR20 readout in the all-comers population had been muted by subjective-score variability.

The combined imaging, joint-count and biomarker package gave SynAct three deliverables that the primary endpoint alone could not:

1. A defensible scientific narrative for the elevated-CRP subgroup that SynAct subsequently carried into the ACR Convergence 2024 presentation and used as the design basis for the ongoing ADVANCE Phase 2b study in newly diagnosed RA with hsCRP > 3 mg/L (SynAct ACR 2024 release).
2. Independent, quantitative confirmation that resomelagon engages synovial inflammation in the joints that drive HAQ-DI hand-function improvement, a signal not visible in subjective VAS-driven scores.
3. A blueprint for the RESOLVE program, which carried DEMRIQ + RAMRIS forward as the Part B imaging sub-study in DMARD-IR patients (SynAct Q2 2023 report).

DCE-MRI quantified through DEMRIQ on DYNAMIKA™ delivers a continuous, observer-light readout of synovial inflammation that has been shown — in baricitinib, certolizumab pegol and apremilast programs, to detect dose-response, treatment effect and joint-level resolution earlier and more sensitively than RAMRIS or DAS28 alone (Eur J Radiol, 2021; ACR Abstracts MARVELOUS; ACR Abstracts MOSAIC).

Centralized acquisition standardization and QC are not optional, they are what unlock the published sensitivity.

For early- and mid-stage RA trials, an objective imaging tertiary endpoint provides crucial protection against subjective-score variability and a mechanism-aligned bridge to circulating biomarkers.

For nearly 20 years, Image Analysis Group (IAG) has been a trusted imaging partner to the world’s leading pharma, biotech and medtech companies. With 700+ trials behind us, our imaging CRO (iCRO) combines deep medical imaging science, expert radiology readers, global project management organization and the DYNAMIKA™ platform to de-risk clinical development and accelerate clinical trials.

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Prepared by Image Analysis Group (IAG). For partnership enquiries on quantitative MRI endpoints in rheumatology, MSK and inflammation program, contact the IAG Imaging Experts team: contact@www.ia-grp.com