Immunology's Next Frontier: High-Risk, High-Reward Innovations From EULAR 2025

By Maria Stanica, Gaja Gasiorek, and Pooja Goyal, Lifescience Dynamics

The 2025 European Congress of Rheumatology (EULAR) showcased a transformative shift in the landscape of immunology, highlighting a convergence of next-generation mechanisms and novel therapeutic modalities poised to redefine the management of autoimmune diseases. Emerging strategies, including precision cytokine inhibitors, oral agents, and advanced cellular therapies, underscore an evolving therapeutic landscape that aims to achieve deep remission while challenging the traditional paradigms that have long relied on chronic immunosuppression.

At this year’s congress, the spotlight turned to first-in-class agents and disruptive modalities, particularly in conditions like systemic lupus erythematosus (SLE) and myositis, which have historically lacked effective and durable treatments. These advances signal a new frontier — one that carries substantial scientific and commercial risk, but with it, the potential to advance expectations for efficacy, durability, and disease modification.

Targeting Innate Immunity: TLR7/8 And JAK/ROCK Inhibition

One of the most closely watched presentations at EULAR 2025 highlighted enpatoran (Merck KGaA), a selective Toll-like receptor 7/8 (TLR7/8) inhibitor in SLE. In the WILLOW Phase 2 trial (LB0004), enpatoran demonstrated meaningful clinical improvements in systemic and previously presented cutaneous lupus manifestations, including significant reductions in rash severity and inflammatory biomarkers. Importantly, the agent showed a clean safety profile with no new signals detected.

TLR7/8 are central components of innate immune activation, particularly in lupus. By targeting this early stage of the immune cascade, enpatoran represents a novel approach distinct from cytokine blockade therapies like AstraZeneca’s Saphnelo, GSK’s Benlysta, and Novartis’ Ianalumab. Currently, the only available oral treatments for SLE are largely limited to antimalarials, corticosteroids, and voclosporin (approved specifically for lupus nephritis), underscoring the potential significance of enpatoran as a new oral therapeutic class for SLE. A likely competitor for enpatoran will be Abbvie’s oral JAK-1 inhibitor Rinvoq, currently in Phase 3 trials for SLE.

Another first-in-class agent, CPL’116 (Celon Pharma), is driving innovation through dual inhibition of JAK1/3 and Rho-associated kinase (ROCK). In a Phase 2 trial for rheumatoid arthritis (OP0193), CPL’116met key endpoints by Week 12, with notable improvements in joint swelling and pain. The dual MoA is strategically designed to simultaneously inhibit immune signaling and cellular migration, aiming to achieve more durable disease control in patients resistant to conventional JAK inhibitors.

These agents exemplify a broader trend at EULAR: precision modulation of immune pathways that sit upstream or outside traditional cytokine signaling cascades — a shift that could lead to less immunosuppression, more specificity, and better long-term tolerability.

Disruptive Modalities: Cell Therapy In Autoimmunity

One of the most disruptive developments presented at EULAR 2025 was the emergence of cell therapies as a treatment strategy in autoimmune disease. Historically reserved for oncology, CAR-T technology is now being explored as a curative modality in conditions like lupus and myositis.

Resecabtagene autoleucel (rese-cel, Cabaletta Bio), a CD19-directed autologous CAR-T, garnered significant attention following new data (OP0202 and OP0316) that demonstrated drug-free remission in lupus and myositis patients, including complete renal responses and steroid discontinuation. Notably, some patients maintained durable remission for several months post-lymphodepletion and a single CAR-T infusion, underscoring the potential for a paradigm shift in autoimmune disease treatment.

Meanwhile, Fate Therapeutics presented first-in-human data on FT819, an off-the-shelf CD19 CAR-T, in patients with SLE (OP0032). Preliminary Phase 1 data indicated promising safety and efficacy, suggesting that scalable, allogeneic CAR-T therapy could become viable for broader B-cell driven autoimmune diseases. The design also eliminates the manufacturing burden associated with autologous cell therapy, addressing a critical barrier to adoption in non-oncology settings.

These developments suggest a move away from lifelong suppression and toward one-time, potentially curative treatments. However, they also introduce significant complexity in terms of pricing, reimbursement, and health system readiness.

The Innovation Tradeoff: High Risk, Higher Reward, and What It Means for Pharma

Pioneering novel mechanisms and modalities in immunology comes with its share of scientific, clinical, and commercial risks:

• Validation hurdles: Unlike IL-17 or JAK inhibition, new mechanisms like TLR7/8 and ROCK require education of regulators, physicians, and payers.
• Trial design complexity: Rare disease populations characterized by small sample sizes, lack of validated endpoints, and biomarker variability can hinder development.
• Commercial unpredictability: CAR-T pricing in oncology may not translate well to autoimmune conditions, where standard-of-care costs are significantly lower.

Nevertheless, the strategic upside is profound. As seen with early TNF inhibitors or IL-23 monoclonal antibodies(mAbs), those who succeed in validating a new mechanism of action (MoA) can shape treatment paradigms for decades and secure first-mover advantage in high-burden, underserved indications.

For pharma leaders and investors, EULAR 2025 offered a strategic signal: innovation at the edge must be pursued alongside multi-indication expansion. While immunology is becoming increasingly indication-agnostic and assets like Sotyktu (Bristol Myers Squibb) are moving from psoriasis to psoriatic arthritis (PsA) to SLE, true differentiation will increasingly depend on first-in-class innovation, particularly in diseases with high unmet need or low biologic penetration. This means rebalancing portfolios: sustaining commercial engines like Tremfya® (Johnson & Johnson) or Rinvoq, while simultaneously incubating riskier, high-reward assets like enpatoran or rese-cel. Partnerships and bolt-on acquisitions may play a key role in sourcing such innovation.

About The Authors:

Maria Stanica (MSc), Gaja Gasiorek (MPhil), and Pooja Goyal (MSPharm) are with Lifescience Dynamics.