Oral TNFR1 Inhibitor Balinatunfib Shows Promise in Psoriasis

At the 2025 European Academy of Dermatology and Venereology (EADV) Congress, a late-breaking session led by Fernando Valenzuela, MD, highlighted new clinical trial data for balinatunfib (SAR441566; Sanofi), an investigational oral inhibitor of TNF receptor 1 (TNFR1).¹ The findings from this randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial shed light on a potential new mechanism of action for patients with moderate to severe psoriasis.

Mechanism of Action

Tumor necrosis factor alpha (TNF-α) is central to psoriasis pathogenesis, acting through 2 distinct receptors. Soluble TNF-α binds mainly to TNFR1 and drives pro-inflammatory signaling and tissue destruction. In contrast, transmembrane TNF-α primarily engages TNFR2, supporting immune regulation and tissue repair. Current anti-TNF biologics inhibit both receptors, which can compromise protective immune functions.²

In contrast, balinatunfib selectively targets soluble TNF-α signaling via TNFR1 while preserving TNFR2 activity. As the presenter explained, “Balinatumab inhibits only the soluble TNF alpha and prevents the TNF receptor 1 signaling while allowing the homeostasis function of the TNF receptor 2 to continue functioning."

Study Design

The trial enrolled adults with moderate to severe plaque psoriasis, defined as PASI ≥12, sPGA ≥3, and body surface area involvement ≥10%. Participants were divided into 2 cohorts: treatment-naïve patients with no prior systemic or biologic exposure, and treatment-experienced patients who had previously received biologics, biosimilars, or small molecules.

Naïve patients were randomized to 5 different dosing arms or placebo, while experienced patients were assigned to three dosing regimens or placebo. The primary endpoint was the proportion of patients achieving PASI 75 at week 12 in the naïve cohort. Secondary endpoints included sPGA 0/1 response and overall safety.

Efficacy Results

While the 200 mg twice-daily dose did not achieve statistical significance for the primary endpoint in the naïve cohort, encouraging signals emerged across other groups. “We did not create statistically significance on this particular dosage. However, you can see that we have nominal statistically significant in the mixed population on 200 milligrams, twice daily, and 200 milligrams once daily. And in the naïve population, we also had nominal, statistically significant in 100 twice daily," Valenzuela said.

Responses were observed as early as week 4, with improvements continuing through week 12. Patients on active treatment also achieved higher rates of PASI 90 compared to placebo. Importantly, exploratory biomarker analysis demonstrated reductions in IL-17A, IL-17F, IL-22, and IL-19, further supporting the mechanism of TNFR1 blockade.

Patient-Reported Outcomes

Quality of life improvements, as measured by the Dermatology Life Quality Index (DLQI), were reported in both naïve and mixed cohorts. These patient-centered outcomes add weight to the clinical and biomarker findings, reflecting the potential day-to-day benefits of oral TNFR1 inhibition.

Safety Profile

Overall, balinatunfib was well tolerated. The most common adverse events, occurring in >5% of participants, included nausea, parotitis, and arthralgia, which also appeared in placebo groups. A small number of serious adverse events were reported but were not directly related to the investigational drug.

Expert Discussion

During the Q&A, investigators acknowledged limitations of the study, particularly the sample size and relatively short 12-week duration. As Valenzuela emphasized, “This is a phase 2 so we will not have a huge amount of patients to really have a scientific answer to this question, but I think that [efficacy] can be a little comparable with some of the like weakest [TNF blockers]."

The question of how balinatunfib may perform in patients who failed prior TNF inhibitors remains open. Although some experienced patients were included, subgroup analyses were insufficient to draw firm conclusions.

Conclusion

This late-breaking session at EADV 2025 introduced promising phase 2b data for balinatunfib, a first-in-class oral TNFR1-selective inhibitor. While the primary endpoint was not met at the prespecified dose in treatment-naïve patients, signals of efficacy, biomarker reductions, and favorable safety outcomes suggest potential for further development. Larger and longer studies will be essential to confirm these findings and define the clinical role of TNFR1 inhibition in psoriasis management.

References

1. Valenzuela F. Balinatunfib, the first oral selective inhibitor of TNFR1 signaling in plaque psoriasis: a double-blind, randomized, placebo-controlled phase 2b study. Presented at: 2025 European Academy of Dermatology and Venerology Congress; September 17-20; Paris, France.
2. Chima M, Lebwohl M. TNF inhibitors for psoriasis. Semin Cutan Med Surg. 2018;37(3):134-142. doi:10.12788/j.sder.2018.039