A pivotal clinical trial has revealed promising results for a novel gene therapy approach in treating recurrent respiratory papillomatosis (RRP), a rare but challenging condition caused by human papillomavirus (HPV) infection. The study, conducted at the NIH Center for Immuno-Oncology, demonstrated that the experimental treatment PRGN-2012 achieved complete response in 51% of treated patients.
Significant Clinical Outcomes
The trial enrolled 35 patients who received the recommended phase II dose of PRGN-2012. Among these participants, 18 patients (51%) achieved complete response, defined as requiring no clinically indicated interventions for a full year following treatment. This outcome is particularly noteworthy given that these patients had previously required a median of four surgical interventions, with some needing up to 10 procedures in the year before treatment.
The durability of response proved impressive, with 83% of responders maintaining their response beyond the initial 12-month period, reaching a median follow-up of 22 months. The median duration of complete response had not been reached at the 12-month follow-up point.
Treatment Approach and Safety Profile
PRGN-2012 utilizes a gorilla adenovirus vector to deliver gene therapy designed to stimulate robust T-cell immunity specific to HPV 6 or 11, the primary viral subtypes responsible for RRP. The treatment protocol involved:
- Initial standard surgery at baseline
- Four subcutaneous administrations over 12 weeks
- Up to two optional debulking surgeries during the treatment period if needed
The safety profile proved favorable, with no serious adverse events or grade 3 or worse treatment-related complications reported. Most side effects were mild, primarily consisting of:
- Injection site reactions (97%)
- Fatigue (80%)
- Chills (71%)
- Fever (69%)
Disease Impact and Current Treatment Landscape
RRP affects approximately two per 100,000 persons in the United States, causing persistent papillomas primarily in the larynx, trachea, and lungs. Traditional management involves repeated laser ablation and surgical excision of papillomas, which can lead to irreversible airway damage over time. Previous attempts with nonspecific immunotherapies have shown limited success.
Dr. Craig Derkay of Eastern Virginia Medical School, in an accompanying editorial, characterized the results as "potentially game-changing" for adults with severe RRP. He emphasized that any intervention reducing surgery necessity represents a breakthrough, given the current lack of licensed therapeutics for this disorder.
Future Directions and Research
While the results are promising, some questions remain unanswered. The researchers noted that without biopsy confirmation of complete HPV clearance in responding patients, it's uncertain whether the treatment provides a cure. Phase III trials are being planned to:
- Confirm the durability of results
- Evaluate the potential benefit of booster doses
- Identify factors affecting treatment response
- Explore combination therapies with immune-checkpoint inhibitors or bevacizumab biosimilars
The study's findings will support an FDA application for accelerated approval as the first systemic treatment for adult RRP, potentially marking a significant advancement in managing this challenging condition.
