TNFR1 ‐selective inhibition in psoriasis: Interpreting early clinical findings from a phase 1 trial

Anti-TNF biologics were the first biological therapies to significantly transform psoriasis treatment. Their approval in the mid-2000s marked a major turning point in psoriasis management and changed both physicians' and patients' expectations. Although some required intravenous infusions and others relatively frequent injections, the clinical improvements they achieved were remarkable and led to their widespread adoption in clinical practice. Over time, these therapies not only improved disease control but also expanded understanding of psoriasis immunopathology. TNF has been identified as one of the key mediators of inflammation in psoriasis, and its inhibition represents a significant therapeutic strategy.1 However, conventional anti-TNF biologics inhibit both TNFR1 and TNFR2, and this non-selective blockade has been associated with limitations, including an increased risk of infections and malignancies.2 Increasing knowledge of TNF biology has shown that these receptors may have distinct and sometimes opposing biological functions. TNFR1 signalling primarily mediates proinflammatory pathways, whereas TNFR2 is associated with immune regulation and tissue repair.2, 3 These insights raised the question of whether more selective therapeutic strategies could represent a new direction in TNF-targeted therapy. In this context, the selective inhibition of TNFR1 has been identified as a promising therapeutic concept. Targeting TNFR1 while preserving TNFR2 signalling could reduce inflammatory responses while maintaining beneficial immune functions.2, 3 This concept has attracted attention as a potential strategy for developing more selective anti-TNF therapies. Alongside these developments, the search for effective oral therapies in psoriasis has continued. While biologics have transformed disease outcomes, many patients still prefer oral medications. In recent years, increasing attention has focused on targeted oral small molecules, such as PDE-4 inhibitors and TYK2 inhibitors, which aim to combine oral administration with more selective immunomodulatory effects.4 Reflecting these developments, the article by Nassr et al.5 in this issue of the journal reports early clinical findings on balinatunfib, an orally administered small molecule designed to selectively inhibit TNFR1 signalling. In this phase 1 randomized placebo-controlled study, the authors evaluated safety, tolerability and preliminary clinical responses in patients with mild-to-moderate plaque psoriasis. The results indicate that balinatunfib was generally well tolerated, with no severe or serious treatment-emergent adverse events reported during the short study period. Exploratory analyses also suggested improvements in clinical parameters compared with placebo. These findings provide early clinical support for the feasibility of TNFR1-selective inhibition. However, the results should be interpreted within the context of the study design. As acknowledged by the authors, the relatively small sample size, short study duration and inclusion of patients with mild-to-moderate psoriasis represent inherent limitations of this early-phase trial. Another important point reported by the authors is that a larger phase 2b multicentre trial including a broader and more diverse psoriasis population was conducted to further assess safety and efficacy; however, clinical development of balinatunfib as a monotherapy for psoriasis was ultimately discontinued, likely due to insufficient clinical efficacy. At first glance, this outcome may appear discouraging; however, the limited efficacy in psoriasis does not necessarily invalidate the concept of TNFR1-selective inhibition, but rather reflects the complexity of disease pathophysiology and suggests that translating this mechanism into clinical benefit may not be straightforward. Nevertheless, TNFR1 signalling remains an important pathway in inflammatory diseases. As highlighted by the authors, ongoing phase 2 studies are currently investigating balinatunfib in other immune-mediated conditions, including rheumatoid arthritis, ulcerative colitis and Crohn's disease. From this perspective, selective TNFR1 inhibition may still represent a worthwhile therapeutic strategy in diseases where this pathway plays a more prominent role. Although the development of balinatunfib for psoriasis has been discontinued, this study provides early clinical insights that may help inform future research in other inflammatory diseases. The author has nothing to report. SSS has received speaking fees and/or travel support from AbbVie, Janssen, Novartis and UCB, outside the submitted work. Not applicable. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.