RP1

Overview

Vusolimogene oderparepvec (RP1) is an investigational, intratumorally injected, herpes simplex virus type 1 (HSV‑1)–based oncolytic immunotherapy engineered to enhance direct tumor lysis and stimulate systemic anti‑tumor immunity. It has been studied most extensively in advanced melanoma (often after anti–PD‑1 failure) in combination with nivolumab, and in other skin cancers. On July 22, 2025, the FDA issued a Complete Response Letter declining accelerated approval for RP1+nivolumab in advanced melanoma; no safety issues were cited, and the agency’s concern centered on the adequacy and interpretability of the single‑arm IGNYTE trial. Replimune held a Type A meeting with FDA on September 16, 2025 to discuss next steps. (ir.replimune.com)

Mechanism of action

• Backbone and edits: RP1 is derived from a potent clinical HSV‑1 strain with deletions in ICP34.5 (to confer tumor-selective replication) and ICP47 (to enhance antigen presentation via increased US11 expression). (pubmed.ncbi.nlm.nih.gov)
• Transgenes: RP1 encodes human GM‑CSF and a truncated, constitutively fusogenic gibbon ape leukemia virus envelope glycoprotein (GALV‑GP R‑). The fusogenic protein promotes tumor cell–cell fusion and immunogenic cell death, increasing antigen release and innate/adaptive immune activation; preclinical models show enhanced local and abscopal anti‑tumor effects and synergy with PD‑1 blockade. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Advanced melanoma after anti–PD‑1 therapy (IGNYTE, phase 1/2, single‑arm RP1 + nivolumab) - Population: 156 patients (46% previously received ipilimumab+nivolumab; 51% stage IVM1b–d). (ascopubs.org) - Objective response rate (ORR): 31.4%; complete response (CR): 12.2% (investigator‑assessed). Responses occurred in injected and uninjected (including visceral) lesions; median duration of response >24 months at the Nov 6, 2023 cutoff with 78% ongoing. (ascopubs.org)

Confirmatory/outcomes studies under way - IGNYTE‑3 (phase 3): randomized RP1+nivolumab vs physician’s choice in advanced melanoma progressing on anti–PD‑1±anti–CTLA‑4; primary endpoint overall survival. (Trial registration NCT06264180.) (ascopubs.org)

Non‑melanoma skin cancers - Early IGNYTE cohort in anti–PD‑1‑failed non‑melanoma skin cancers (mixed tumor types): preliminary ORR ~30% (company report; early, non‑comparative). (ir.replimune.com) - CERPASS (phase 2, randomized cemiplimab ± RP1 in advanced cutaneous squamous cell carcinoma): did not meet co‑primary endpoints (ORR and CR rate by blinded review), though CR rate numerically higher with RP1+cemo (38.1% vs 25%); additional endpoints maturing. (Top‑line company disclosure.) (globenewswire.com)

Immunocompromised (transplant recipients) - ARTACUS (phase 1/2, single‑arm RP1 monotherapy): interim analyses reported ORR 34.8% (8/23 evaluable; 5 CRs) with no observed allograft rejection to the data cutoff; conference/company reports. (ir.replimune.com)

Note: Except where specified, the above efficacy results come from meeting abstracts or company communications; peer‑reviewed, fully published clinical outcomes for RP1 in these settings remain limited as of October 2025. (ascopubs.org)

Safety

• In IGNYTE (RP1+nivolumab), treatment‑related adverse events were predominantly grade 1–2 and consistent with expected oncolytic therapy “flu‑like” effects; one grade 5 immune‑mediated myocarditis was attributed to nivolumab. (ascopubs.org)
• In CERPASS, adding RP1 to cemiplimab increased mostly transient grade 1–2 events; isolated grade 3–4 immune‑related events occurred; no grade 5 RP1‑related events were reported in the top‑line analysis. (ir.replimune.com)
• In ARTACUS interim reports (RP1 monotherapy in transplant recipients), RP1 was generally well tolerated without evidence of allograft rejection to the cutoff. (ir.replimune.com)

Further reading

• Development of the RP1 platform and mechanism (J Immunotherapy of Cancer, 2019, peer‑reviewed). (pubmed.ncbi.nlm.nih.gov)
• IGNYTE melanoma cohort results (ASCO 2024 abstract). (ascopubs.org)
• IGNYTE‑3 phase 3 design (ASCO 2024 abstract). (ascopubs.org)
• ARTACUS transplant study design and interim results (ASCO abstract; company update). (ascopubs.org)
• CERPASS randomized CSCC study (ASCO trial-in-progress abstract; top‑line results). (ascopubs.org)
• FDA regulatory updates: BLA acceptance/priority review and Complete Response Letter (company releases; trade coverage). (ir.replimune.com)

If additional peer‑reviewed publications of clinical outcomes become available, those should supersede the meeting‑abstract and company‑reported figures summarized here.

Last updated: Oct 2025