PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis: a pivotal phase 1/2 clinical trial.

Background: Recurrent respiratory papillomatosis (RRP) is a rare debilitating condition caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Papillomas develop in the aerodigestive tract, leading to significant voice disturbance and airway obstruction. No systemic treatment currently exists. We aimed to assess the safety and clinical activity of PRGN-2012 in adult patients with RRP treated at the recommended phase 2 dose.

Methods: This was a single-centre, single-arm, phase 1/2 trial. Adult patients aged 18 years or older with RRP who required three or more interventions in the 1 year before treatment received adjuvant PRGN-2012 on day 1 following surgical debulking of disease, and on days 15, 43, and 85. Primary outcome measure was complete response rate, defined as the percentage of patients who did not require an intervention to control RRP in the 12 months after treatment. Safety outcomes included treatment-related adverse events. This study is registered ClinicalTrials.gov (NCT04724980).

Findings: From March 16, 2021, to June 1, 2023, 38 patients were enrolled and received the 12-week treatment course. Among the 35 patients treated at the recommended phase 2 dose of 5×10 particle units, 18 (51%) of 35 patients had a complete response (95% CI 34-69) with the median duration of complete response yet to be reached. Adverse events were mild and included grades 1-2 injection site reaction (34 [97%] of 35), fatigue (28 [80%] of 35), chills (25 [71%] of 35), and fever (24 [69%] of 35).

Interpretation: PRGN-2012 treatment resulted in complete response in 51% of the patients treated and was safe. Based on these positive pivotal study results, a biologics license application to the US Food and Drug Administration (FDA) is planned, positioning PRGN-2012 to be an FDA-approved medical treatment for adult patients with RRP.

Funding: National Institutes of Health.