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Background Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Significant morbidity can occur due to airway obstruction and transformation into malignant cancer can occur. Zopapogene imadenovec (PAPZIMEOSTM) , a novel HPV-Targeted Immuno-Activator, is the first and only FDA-approved treatment for adults with RRP, and set to be the new standard of care treatment.Methods The pivotal trial ( NCT04724980) evaluated safety and efficacy in adult patients with RRP treated with 4 subcutaneous injections of zopapogene imadenovec (5x1011 particle units per injection; n=35). Zopapogene imadenovec was well-tolerated, with no serious adverse events, no grade >2 treatment-related adverse events, and no early treatment discontinuations. Most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. Robust efficacy was observed following the treatment, with 51.4% (95% CI: 34.0 to 68.6) of patients achieving a Complete Response (CR), defined as no requirement for interventions in the 12m following treatment and 86% (30/35) of patients experienced a decrease in interventions.Results As of March 20, 2025, median duration of follow-up for all 35 patients was 30.3m (5 – 36). No new safety events were observed during long-term follow-up.Of 18 initial protocol-defined CRs, 15 (83%) remain in CR with median duration of follow-up of 34m (24-36). Median duration of CR has yet to be reached. 58% (95% CI: 39.1 to 75.5; n=31) and 83% (95% CI: 51.6 to 97.9; n=12) of evaluable patients did not require any interventions in year (Y) 2 and Y3 respectively. 90% and 91% of evaluable patients experienced a decrease in the number of interventions in Y2 and Y3 respectively compared to their 12m pre-treatment period.The development of HPV-specific T cell response post treatment assessed via IFN-γ ELISpot assay demonstrated that zopapogene imadenovec treatment stimulates the induction of HPV-specific T-cells and the magnitude of T-cell response was significantly higher in patients achieving CR or Partial Response compared to non-responders (mean fold-change 164.9 vs 5.1, P<0.018).Neutralizing antibody (NAb) titers collected up to 52-weeks post-treatment remained at little to low levels and there was no correlation between NAb incidence or titer and clinical response.Conclusions These data demonstrate that patients treated with zopapogene imadenovec either maintained consistent CRs for up to 3 years or demonstrated a reduction in the need for clinically indicated interventions following recurrence with excellent long-term safety.Ethics Approval The study obtained ethics approval from the NIH Intramural IRB, 6700B Rockledge Drive, Ste. 4300 Bethesda, Maryland USA 20817. The number/ID of the approval(s) are as follows: IRB ID: 21C0013/ MOD002946 IRB ID: 21C0013/ MOD004094 IRB ID: 21C0013/ MOD001703 IRB ID: 21C0013/ MOD002083 IRB ID: 21C0013/ MOD010746 IRB ID: 21C0013/ MOD006823 IRB ID: 21C0013/ MOD002680 IRB ID: All study participants gave informed consent before taking part and were reconsented according to the NIH IRB guidelines.