FDA Grants Accelerated Approval to First Plasmid DNA-Based Immunotherapy for Recurrent Respiratory Papillomatosis

The FDA has granted accelerated approval to doruxapapogene ralaplasmid and lalikinogene sifuplasmid-gxfd (Voceryq; Inovio Pharmaceuticals) for the treatment of adults with recurrent respiratory papillomatosis (RRP), a rare chronic disease caused by human papillomavirus (HPV). The decision marks the first US approval of a plasmid DNA-based immunotherapy.¹

“Adults living with RRP often face an exhausting and relentless cycle of repeated surgeries, managing their disease, but never truly escaping it,” Karim Mikhail, BPharm, MS, director of the FDA’s Center for Biologics Evaluation and Research, said in a news release. “For patients, that could mean fewer surgeries, fewer disruptions, and more time living their lives on their own terms.”¹

Understanding Recurrent Respiratory Papillomatosis

RRP occurs when HPV types 6 and/or 11 drive the formation of benign, wart-like papillomas in the airway, most often around the vocal cords. Individuals with RRP may experience hoarseness, chronic cough, and voice changes. Severe disease can spread through the respiratory tract and impair breathing. Because the virus persists after papillomas are removed, growths frequently return, requiring repeated procedures over many years. In some cases, RRP carries a risk of malignant transformation.¹

The disease is rare. A 2024 systematic literature review reported adult-onset RRP incidence ranging from 0.2 to 3.9 per 100,000 and prevalence ranging from 0.4 to 8.4 per 100,000. The review also found that, where data were available, national prophylactic HPV vaccination programs were associated with significantly lower incidence of juvenile-onset disease.²

Mechanism of Action

Doruxapapogene ralaplasmid and lalikinogene sifuplasmid deliver 2 plasmids into the body’s cells: one encodes specific HPV-6 and HPV-11 proteins, and the other encodes IL-12, an immune response-enhancing molecule. Together, they are designed to prompt the immune system to attack HPV-infected cells.¹

The therapy is administered via an intramuscular injection using the CELLECTRA 5PSP device, which administers the dose and performs electroporation, a technique that uses brief electrical pulses to temporarily open pores in cell membranes so the plasmids can enter cells. In the pivotal trial, patients received 4 doses.^1,3

Clinical Trial Results

The approval is based on an open-label, multicenter phase 1/2 trial (NCT04398433) that enrolled 32 adults with HPV-6– and/or HPV-11–associated RRP. Eligible patients had undergone at least 2 papilloma removal surgeries in the 12 months before treatment, including a scheduled surgery at trial entry. Among 26 patients with at least 3 baseline surgeries, 7 (27%) required no surgical intervention in the first year after treatment.^1,3

Across the full trial population, 81% (26 of 32) of patients needed fewer surgeries in the year after treatment compared with the year before. Investigators also observed induction of HPV-6– and HPV-11–specific T cells in peripheral blood, and T-cell receptor sequencing confirmed that newly emerged T-cell clones trafficked to papilloma tissue.³

A retrospective follow-up of 28 original patients suggested the effect may deepen over time. The mean number of surgeries fell from about 4.1 in the year before treatment to 1.7 in year 1 and 0.9 in year 2, and the proportion of patients requiring no surgeries rose from 28% to 50%. There were no serious adverse events (AEs) or long-term safety concerns identified.⁴

Because the FDA considers reduced surgical frequency an intermediate clinical end point reasonably likely to predict clinical benefit, the manufacturer must complete postapproval trials to verify the therapy’s clinical benefit.¹

Safety Considerations

The most commonly reported AEs were injection site reactions, headache, fatigue, hypertension, nausea, and dizziness. The FDA noted that AEs associated with electroporation may include brief muscle contractions or tetany, temporary bleeding at the administration site, anxiety, vasovagal reactions, transient changes in creatine phosphokinase, and injection site erythema and pain.¹

Clinical Implications for Pharmacists

Until recently, RRP management relied entirely on surgery. In August 2025, the FDA approved zopapogene imadenovec-drba (Papzimeos; Precigen), a nonreplicating adenoviral vector-based immunotherapy, as the first therapy for adults with RRP. Doruxapapogene ralaplasmid and lalikinogene sifuplasmid offer a second, mechanistically distinct option built on plasmid DNA rather than a viral vector.^1,5

Pharmacists in specialty and health-system settings can help prepare patients for electroporation-based administration, including the possibility of transient muscle contractions and vasovagal reactions. Pharmacists can also reinforce HPV vaccination as a prevention strategy, given its association with lower rates of juvenile-onset disease.²

Looking Ahead

The FDA granted doruxapapogene ralaplasmid and lalikinogene sifuplasmid breakthrough therapy and orphan drug designations. Confirmatory trial results will ultimately define its place in therapy alongside zopapogene imadenovec and surgical management.¹

REFERENCES

1. FDA approves first plasmid DNA-based immunotherapy for adults with recurrent respiratory papillomatosis. News release. FDA. October 30, 2026. Accessed November 2, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-plasmid-dna-based-immunotherapy-adults-recurrent-respiratory-papillomatosis

2. Ovcinnikova O, Engelbrecht K, Verma M, et al. A systematic literature review of the epidemiology, clinical, economic and humanistic burden in recurrent respiratory papillomatosis. Respir Res. 2024. doi:10.1186/s12931-024-03057-w

3. Morrow MP, Gillespie E, Sylvester A, et al. DNA immunotherapy for recurrent respiratory papillomatosis (RRP): phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107. Nat Commun. 2025;16(1):1518. doi:10.1038/s41467-025-56729-6

4. Amin MR, Belafsky PC, Best SR, et al. DNA immunotherapy (INO-3107) results in long-term surgery reduction in recurrent respiratory papillomatosis. Laryngoscope. 2025;135(11):4287-4295. doi:10.1002/lary.32416

5. FDA approves first immunotherapy for recurrent respiratory papillomatosis. News release. FDA. August 14, 2025. Accessed November 2, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-recurrent-respiratory-papillomatosis