Editorial: Gene Silencing Therapy for a New Era of Pancreatitis Prevention. Authors' Reply

We commend Dr Petrov for a thoughtful and forward-looking editorial that reframes pancreatitis prevention as a longitudinal, mechanistically informed discipline rather than a purely episodic, hospital-based endeavour [1]. The rising global burden of acute pancreatitis (AP) [2], together with its increasingly recognised long-term sequelae, underscores the urgency of advancing prevention strategies beyond their historically narrow scope. As highlighted in the editorial, recurrent AP remains understudied. The emerging evidence that recurrent AP confers long-term risk [3-5] substantially elevates its clinical importance and strengthens the case for earlier, proactive intervention. We agree that targeting hypertriglyceridaemia (HTG) represents a biologically compelling and clinically actionable approach to primary prevention in selected populations. Apolipoprotein C-III (APOC3) occupies a central regulatory position in triglyceride (TG) metabolism through inhibition of both lipoprotein lipase-dependent and lipoprotein lipase-independent lipolysis and clearance of triglyceride-rich lipoproteins (TRL) [6]. Genetic [7], mechanistic [6] and clinical data [8-11] collectively support APOC3 as a rational therapeutic target in conditions characterised by severe or refractory HTG. The study with plozasiran, an siRNA therapeutic now approved as Redemplo in the United States, Canada and China as an adjunct to diet to reduce TGs in adults with familial chylomicronaemia syndrome (FCS), represents an important conceptual and clinical advance [12]. Despite its modest sample size—inevitable in rare disease research—the magnitude and rapidity of TG lowering, coupled with the known associated reduction in pancreatitis risk, provide a strong rationale for broader investigation. The inclusion of patients without genetically confirmed familial chylomicronaemia syndrome (FCS) further strengthens the evidence of the therapeutic implications extending beyond monogenic disease. At the same time, the field would benefit from thoughtful delineation of the populations most likely to derive benefit from triglyceride-lowering interventions aimed at pancreatitis prevention. While very severe HTG is a well-established risk factor for pancreatitis, the TG thresholds, trajectories and modifiers that meaningfully influence the risk of its recurrence in more heterogeneous clinical settings remain incompletely defined. Future trials will therefore need to balance mechanistic ambition with pragmatic design, incorporating appropriate baseline risk stratification and clinically relevant endpoints. Of interest, studies with plozasiran that are powered for pancreatitis-related endpoints—not solely lipid parameters—are in process and will be essential to establishing clinical utility. In this context, the editorial serves as a timely and constructive call to action, and successful integration into clinical practice will depend on rigorous clinical investigation, careful patient selection and sustained collaboration across gastroenterology, lipidology, cardiology and endocrinology. Rohit Loomba: conceptualization, writing – original draft, writing – review and editing. Enrique de-Madaria: writing – review and editing. Elham Afghani: writing – review and editing. Vikesh K. Singh: writing – review and editing. Nicholas J. Leeper: conceptualization, writing – original draft, writing – review and editing. The authors' declarations of personal and financial interests are unchanged from those in the original article [12]. This work was supported by Arrowhead Pharmaceuticals. The authors declare no conflicts of interest. This article is linked to Loomba et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70662 and https://doi.org/10.1111/apt.70623. The data that support the findings of this study are available from the corresponding author upon reasonable request.